-
Tuesday, July 09, 2024
Author(s): Alexandra Weiss,James W Gilbert,Iris Valeria Rivera Flores,Jillian Belgrad,Chantal Ferguson,Elif O Dogan,Nicholas Wightman,Kit Mocarski,Dimas Echeverria,Ashley Summers,Brianna Bramato,Nicholas McHugh,Raymond Furgal,Nozomi Yamada,David Cooper,Kathryn Monopoli,Bruno M D C Godinho,Matthew R Hassler,Ken Yamada,Paul Greer,Nils Henninger,Robert H Brown,Anastasia Khvorova
Source: bioRxiv : the preprint server for biology
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene lowering a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and...
-
Tuesday, July 02, 2024
Author(s): Sarah Opie-Martin,Alfredo Iacoangeli,Simon D Topp,Olubunmi Abel,Keith Mayl,Puja R Mehta,Aleksey Shatunov,Isabella Fogh,Harry Bowles,Naomi Limbachiya,Thomas P Spargo,Ahmad Al-Khleifat,Kelly L Williams,Jennifer Jockel-Balsarotti,Taha Bali,Wade Self,Lyndal Henden,Garth A Nicholson,Nicola Ticozzi,Diane McKenna-Yasek,Lu Tang,Pamela J Shaw,Adriano Chio,Albert Ludolph,Jochen H Weishaupt,John E Landers,Jonathan D Glass,Jesus S Mora,Wim Robberecht,Philip Van Damme,Russell McLaughlin,Orla Hardiman,Leonard van den Berg,Jan H Veldink,Phillippe Corcia,Zorica Stevic,Nailah Siddique,Vincenzo Silani,Ian P Blair,Dong-Sheng Fan,Florence Esselin,Elisa de la Cruz,William Camu,Nazli A Basak,Teepu Siddique,Timothy Miller,Robert H Brown,Ammar Al-Chalabi,Christopher E Shaw
Source: Nature communications
No abstract
-
Thursday, June 27, 2024
Author(s): Dilara O Halim,Gopinath Krishnan,Evan P Hass,Soojin Lee,Mamta Verma,Sandra Almeida,Yuanzheng Gu,Deborah Y Kwon,Thomas G Fazzio,Fen-Biao Gao
Source: Cell reports
GGGGCC (G(4)C(2)) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this genetic mutation leads to neurodegeneration remains largely unknown. Using CRISPR-Cas9 technology, we deleted EXOC2, which encodes an essential exocyst subunit, in induced pluripotent stem cells (iPSCs) derived from C9ORF72-ALS/FTD patients. These cells are viable owing to the presence of truncated EXOC2, suggesting that exocyst...
-
Monday, June 10, 2024
Author(s): Paul J Hop,Dongbing Lai,Pamela J Keagle,Desiree M Baron,Brendan J Kenna,Maarten Kooyman,None Shankaracharya,Cheryl Halter,Letizia Straniero,Rosanna Asselta,Salvatore Bonvegna,Alexandra I Soto-Beasley,Project MinE ALS Sequencing Consortium,Zbigniew K Wszolek,Ryan J Uitti,Ioannis Ugo Isaias,Gianni Pezzoli,Nicola Ticozzi,Owen A Ross,Jan H Veldink,Tatiana M Foroud,Kevin P Kenna,John E Landers
Source: Nature genetics
Despite substantial progress, causal variants are identified only for a minority of familial Parkinson's disease (PD) cases, leaving high-risk pathogenic variants unidentified^(1,2). To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32 as a novel PD gene identifying c.213C G/p.S71R as a high-risk variant presenting in ~0.7% of familial PD cases while observed in only 0.004% of...
-
Wednesday, May 22, 2024
Author(s): Gizem Taş,Timo Westerdijk,Eric Postma,Project MinE ALS GWAS Consortium,Jan H Veldink,Alexander Schönhuth,Marleen Balvert
Source: Bioinformatics (Oxford, England)
MOTIVATION: The completion of the genome has paved the way for genome-wide association studies (GWAS), which explained certain proportions of heritability. GWAS are not optimally suited to detect non-linear effects in disease risk, possibly hidden in non-additive interactions (epistasis). Alternative methods for epistasis detection using, e.g. deep neural networks (DNNs) are currently under active development. However, DNNs are constrained by finite computational resources, which can be rapidly...
-
Wednesday, May 22, 2024
Author(s): Heather Marriott,Thomas P Spargo,Ahmad Al Khleifat,Peter M Andersen,Nazli A Başak,Johnathan Cooper-Knock,Philippe Corcia,Philippe Couratier,Mamede de Carvalho,Vivian Drory,Marc Gotkine,John E Landers,Russell McLaughlin,Jesús S Mora Pardina,Karen E Morrison,Susana Pinto,Christopher E Shaw,Pamela J Shaw,Vincenzo Silani,Nicola Ticozzi,Philip van Damme,Leonard H van den Berg,Patrick Vourc'h,Markus Weber,Jan H Veldink,Project MinE ALS Sequencing Consortium,Richard J Dobson,Patrick Schwab,Ammar Al-Chalabi,Alfredo Iacoangeli
Source: Annals of clinical and translational neurology
OBJECTIVE: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk.
-
Wednesday, April 17, 2024
Author(s): Rabi Tawil,Kathryn R Wagner,Johanna I Hamel,Doris G Leung,Jeffrey M Statland,Leo H Wang,Angela Genge,Sabrina Sacconi,Hanns Lochmüller,David Reyes-Leiva,Jordi Diaz-Manera,Jorge Alonso-Perez,Nuria Muelas,Juan J Vilchez,Alan Pestronk,Summer Gibson,Namita A Goyal,Lawrence J Hayward,Nicholas Johnson,Samantha LoRusso,Miriam Freimer,Perry B Shieh,S H Subramony,Baziel van Engelen,Joost Kools,Olof Dahlqvist Leinhard,Per Widholm,Christopher Morabito,Christopher M Moxham,Diego Cadavid,Michelle L Mellion,Adefowope Odueyungbo,William G Tracewell,Anthony Accorsi,Lucienne Ronco,Robert J Gould,Jennifer Shoskes,Luis Alejandro Rojas,John G Jiang
Source: The Lancet. Neurology
BACKGROUND: Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38β MAPK) for the treatment of facioscapulohumeral muscular dystrophy.
-
Tuesday, April 09, 2024
Author(s): Stacy R Lindborg,Namita A Goyal,Jonathan Katz,Matthew Burford,Jenny Li,Haggai Kaspi,Natalie Abramov,Bruno Boulanger,James D Berry,Katharine Nicholson,Tahseen Mozaffar,Robert Miller,Liberty Jenkins,Robert H Baloh,Richard Lewis,Nathan P Staff,Margaret Ayo Owegi,Bob Dagher,Netta R Blondheim-Shraga,Yael Gothelf,Yossef S Levy,Ralph Kern,Revital Aricha,Anthony J Windebank,Robert Bowser,Robert H Brown,Merit E Cudkowicz
Source: Muscle & nerve
INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint.
-
Thursday, March 21, 2024
Author(s): Salome Funes,Jonathan Jung,Del Hayden Gadd,Michelle Mosqueda,Jianjun Zhong,None Shankaracharya,Matthew Unger,Karly Stallworth,Debra Cameron,Melissa S Rotunno,Pepper Dawes,Megan Fowler-Magaw,Pamela J Keagle,Justin A McDonough,Sivakumar Boopathy,Miguel Sena-Esteves,Jeffrey A Nickerson,Cathleen Lutz,William C Skarnes,Elaine T Lim,Dorothy P Schafer,Francesca Massi,John E Landers,Daryl A Bosco
Source: Nature communications
Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs...
-
Tuesday, January 30, 2024
Author(s): Md Amin Hossain,Richa Sarin,Daniel P Donnelly,Brandon C Miller,Alexandra Weiss,Luke McAlary,Svetlana V Antonyuk,Joseph P Salisbury,Jakal Amin,Jeremy B Conway,Samantha S Watson,Jenifer N Winters,Yu Xu,Novera Alam,Rutali R Brahme,Haneyeh Shahbazian,Durgalakshmi Sivasankar,Swathi Padmakumar,Aziza Sattarova,Aparna C Ponmudiyan,Tanvi Gawde,David E Verrill,Wensheng Yang,Sunanda Kannapadi,Leigh D Plant,Jared R Auclair,Lee Makowski,Gregory A Petsko,Dagmar Ringe,Nathalie Y R Agar,David J Greenblatt,Mary Jo Ondrechen,Yunqiu Chen,Justin J Yerbury,Roman Manetsch,S Samar Hasnain,Robert H Brown,Jeffrey N Agar
Source: PLoS biology
Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic...
-
Wednesday, October 18, 2023
Author(s): Minggang Fang,Sara K Deibler,Alissa L Nana,Sarat C Vatsavayai,Shahid Banday,You Zhou,Sandra Almeida,Alexandra Weiss,Robert H Brown,William W Seeley,Fen-Biao Gao,Michael R Green
Source: Frontiers in neuroscience
A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the cytoplasmic mislocalization and aggregation of the DNA/RNA-binding protein TDP-43, but how loss of nuclear TDP-43 function contributes to ALS and FTD pathogenesis remains largely unknown. Here, using large-scale RNAi screening, we identify TARDBP, which encodes TDP-43, as a gene whose loss-of-function results in elevated DNA mutation rate and genomic instability. Consistent with this...
-
Tuesday, September 26, 2023
Author(s): Gabriela Toro Cabrera,Katharina E Meijboom,Abbas Abdallah,Helene Tran,Zachariah Foster,Alexandra Weiss,Nicholas Wightman,Rachel Stock,Tania Gendron,Alisha Gruntman,Anthony Giampetruzzi,Leonard Petrucelli,Robert H Brown,Christian Mueller
Source: Gene therapy
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons, causing progressive muscle weakness and respiratory failure. The presence of an expanded hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) is the most frequent mutation causing familial ALS and frontotemporal dementia (FTD). To determine if suppressing expression of C9ORF72 gene products can reduce toxicity, we designed a set of artificial microRNAs (amiRNA) targeting the...
-
Wednesday, August 30, 2023
Author(s): Fabiola Rojas,Rodrigo Aguilar,Sandra Almeida,Elsa Fritz,Daniela Corvalán,Estibaliz Ampuero,Sebastián Abarzúa,Polett Garcés,Armando Amaro,Iván Diaz,Cristian Arredondo,Nicole Cortes,Mario Sanchez,Constanza Mercado,Lorena Varela-Nallar,Fen-Biao Gao,Martin Montecino,Brigitte van Zundert
Source: Frontiers in cell and developmental biology
Astrocytes play a critical role in the maintenance of a healthy central nervous system and astrocyte dysfunction has been implicated in various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). There is compelling evidence that mouse and human ALS and ALS/FTD astrocytes can reduce the number of healthy wild-type motoneurons (MNs) in co-cultures or after treatment with astrocyte conditioned media (ACM), independently of their genotype. A...
-
Thursday, August 24, 2023
Author(s): David S Younger,Robert H Brown
Source: Handbook of clinical neurology
The scientific landscape surrounding amyotrophic lateral sclerosis has shifted immensely with a number of well-defined ALS disease-causing genes, each with related phenotypical and cellular motor neuron processes that have come to light. Yet in spite of decades of research and clinical investigation, there is still no etiology for sporadic amyotrophic lateral sclerosis, and treatment options even for those with well-defined familial syndromes are still limited. This chapter provides a...
-
Wednesday, August 16, 2023
Author(s): Jacob R Mann,Elizabeth D McKenna,Darilang Mawrie,Vasileios Papakis,Francesco Alessandrini,Eric N Anderson,Ryan Mayers,Hannah E Ball,Evan Kaspi,Katherine Lubinski,Desiree M Baron,Liana Tellez,John E Landers,Udai B Pandey,Evangelos Kiskinis
Source: Science advances
Loss-of-function variants in NIMA-related kinase 1 (NEK1) constitute a major genetic cause of amyotrophic lateral sclerosis (ALS), accounting for 2 to 3% of all cases. However, how NEK1 mutations cause motor neuron (MN) dysfunction is unknown. Using mass spectrometry analyses for NEK1 interactors and NEK1-dependent expression changes, we find functional enrichment for proteins involved in the microtubule cytoskeleton and nucleocytoplasmic transport. We show that α-tubulin and importin-β1, two...
-
Tuesday, August 01, 2023
Author(s): Aydan Kahriman,James Bouley,Idil Tuncali,Elif O Dogan,Mariana Pereira,Thuyvan Luu,Daryl A Bosco,Samer Jaber,Owen M Peters,Robert H Brown,Nils Henninger
Source: Brain : a journal of neurology
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative diseases that represent ends of the spectrum of a single disease. The most common genetic cause of FTD and ALS is a hexanucleotide repeat expansion in the C9orf72 gene. Although epidemiological data suggest that traumatic brain injury (TBI) represents a risk factor for FTD and ALS, its role in exacerbating disease onset and course remains unclear. To explore the interplay between traumatic brain...
-
Monday, July 03, 2023
Author(s): Salome Funes,Del Hayden Gadd,Michelle Mosqueda,Jianjun Zhong,Jonathan Jung,None Shankaracharya,Matthew Unger,Debra Cameron,Pepper Dawes,Pamela J Keagle,Justin A McDonough,Sivakumar Boopathy,Miguel Sena-Esteves,Cathleen Lutz,William C Skarnes,Elaine T Lim,Dorothy P Schafer,Francesca Massi,John E Landers,Daryl A Bosco
Source: bioRxiv : the preprint server for biology
Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be fully elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs...
-
Monday, July 03, 2023
Author(s): Adalia H Jun-O'Connell,Eliza Grigoriciuc,Akanksha Gulati,Brian Silver,Kimiyoshi J Kobayashi,Majaz Moonis,Nils Henninger
Source: Frontiers in neurology
CONCLUSION: The utilization of a stroke nurse navigator team reduced unplanned 30-day readmissions in stroke patients treated with thrombolysis. Further studies are warranted to determine the extent of the results of stroke patients not treated with thrombolysis and to better understand the relationship between resource utilization during the transition period from discharge and quality outcomes in stroke.
-
Friday, June 30, 2023
Author(s): Karri Kaivola,Ruth Chia,Jinhui Ding,Memoona Rasheed,Masashi Fujita,Vilas Menon,Ronald L Walton,Ryan L Collins,Kimberley Billingsley,Harrison Brand,Michael Talkowski,Xuefang Zhao,Ramita Dewan,Ali Stark,Anindita Ray,Sultana Solaiman,Pilar Alvarez Jerez,Laksh Malik,Ted M Dawson,Liana S Rosenthal,Marilyn S Albert,Olga Pletnikova,Juan C Troncoso,Mario Masellis,Julia Keith,Sandra E Black,Luigi Ferrucci,Susan M Resnick,Toshiko Tanaka,American Genome Center,International LBD Genomics Consortium,International ALS/FTD Consortium,PROSPECT Consortium,Eric Topol,Ali Torkamani,Pentti Tienari,Tatiana M Foroud,Bernardino Ghetti,John E Landers,Mina Ryten,Huw R Morris,John A Hardy,Letizia Mazzini,Sandra D'Alfonso,Cristina Moglia,Andrea Calvo,Geidy E Serrano,Thomas G Beach,Tanis Ferman,Neill R Graff-Radford,Bradley F Boeve,Zbigniew K Wszolek,Dennis W Dickson,Adriano Chiò,David A Bennett,Philip L De Jager,Owen A Ross,Clifton L Dalgard,J Raphael Gibbs,Bryan J Traynor,Sonja W Scholz
Source: Cell genomics
We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for...
-
Thursday, June 22, 2023
Author(s): Ileana Lorenzini,Eric Alsop,Jennifer Levy,Lauren M Gittings,Deepti Lall,Benjamin E Rabichow,Stephen Moore,Ryan Pevey,Lynette M Bustos,Camelia Burciu,Divya Bhatia,Mo Singer,Justin Saul,Amanda McQuade,Makis Tzioras,Thomas A Mota,Amber Logemann,Jamie Rose,Sandra Almeida,Fen-Biao Gao,Michael Marks,Christopher J Donnelly,Elizabeth Hutchins,Shu-Ting Hung,Justin Ichida,Robert Bowser,Tara Spires-Jones,Mathew Blurton-Jones,Tania F Gendron,Robert H Baloh,Kendall Van Keuren-Jensen,Rita Sattler
Source: Frontiers in cellular neuroscience
While motor and cortical neurons are affected in C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), it remains largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We differentiated C9orf72 ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, C9orf72 ALS/FTD iPSC-MG mono-cultures form G(4)C(2) repeat RNA foci, exhibit reduced C9orf72 protein...
-
Sunday, May 28, 2023
Author(s): Melanie Quintana,Benjamin R Saville,Matteo Vestrucci,Michelle A Detry,Lori Chibnik,Jeremy Shefner,James D Berry,Marianne Chase,Jinsy Andrews,Alexander V Sherman,Hong Yu,Kristin Drake,Merit Cudkowicz,Sabrina Paganoni,Eric A Macklin,HEALEY ALS Platform Trial Study Group
Source: Annals of neurology
Platform trials allow efficient evaluation of multiple interventions for a specific disease. The HEALEY ALS Platform Trial is testing multiple investigational products in parallel and sequentially in persons with amyotrophic lateral sclerosis (ALS) with the goal of rapidly identifying novel treatments to slow disease progression. Platform trials have considerable operational and statistical efficiencies compared with typical randomized controlled trials due to their use of shared infrastructure...
-
Wednesday, April 12, 2023
Author(s): Sien Hilde Van Daele,Matthieu Moisse,Joke J F A van Vugt,Ramona A J Zwamborn,Rick van der Spek,Wouter van Rheenen,Kristel Van Eijk,Kevin Kenna,Philippe Corcia,Patrick Vourc'h,Philippe Couratier,Orla Hardiman,Russell McLaughin,Marc Gotkine,Vivian Drory,Nicola Ticozzi,Vincenzo Silani,Antonia Ratti,Mamede de Carvalho,Jesús S Mora Pardina,Monica Povedano,Peter M Andersen,Markus Weber,Nazli A Başak,Chris Shaw,Pamela J Shaw,Karen E Morrison,John E Landers,Jonathan D Glass,Michael A van Es,Leonard H van den Berg,Ammar Al-Chalabi,Jan Veldink,Philip Van Damme
Source: Brain : a journal of neurology
With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small...
-
Thursday, April 06, 2023
Author(s): Fulya Akçimen,Elia R Lopez,John E Landers,Avindra Nath,Adriano Chiò,Ruth Chia,Bryan J Traynor
Source: Nature reviews. Genetics
Recent advances in sequencing technologies and collaborative efforts have led to substantial progress in identifying the genetic causes of amyotrophic lateral sclerosis (ALS). This momentum has, in turn, fostered the development of putative molecular therapies. In this Review, we outline the current genetic knowledge, emphasizing recent discoveries and emerging concepts such as the implication of distinct types of mutation, variability in mutated genes in diverse genetic ancestries and...
-
Monday, March 20, 2023
Author(s): Brett N Adey,Johnathan Cooper-Knock,Ahmad Al Khleifat,Isabella Fogh,Philip van Damme,Philippe Corcia,Philippe Couratier,Orla Hardiman,Russell McLaughlin,Marc Gotkine,Vivian Drory,Vincenzo Silani,Nicola Ticozzi,Jan H Veldink,Leonard H van den Berg,Mamede de Carvalho,Susana Pinto,Jesus S Mora Pardina,Mónica Povedano Panades,Peter M Andersen,Markus Weber,Nazli A Başak,Christopher E Shaw,Pamela J Shaw,Karen E Morrison,John E Landers,Jonathan D Glass,Patrick Vourc'h,Richard J B Dobson,Gerome Breen,Ammar Al-Chalabi,Ashley R Jones,Alfredo Iacoangeli
Source: Frontiers in cellular neuroscience
Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue...
-
Friday, March 10, 2023
Author(s): Allison A Dilliott,Ahmad Al Nasser,Marwa Elnagheeb,Jennifer Fifita,Lyndal Henden,Ingrid M Keseler,Steven Lenz,Heather Marriott,Emily Mccann,Maysen Mesaros,Sarah Opie-Martin,Emma Owens,Brooke Palus,Justyne Ross,Zhanjun Wang,Hannah White,Ammar Al-Chalabi,Peter M Andersen,Michael Benatar,Ian Blair,Johnathan Cooper-Knock,Elizabeth A Harrington,Jeannine Heckmann,John Landers,Cristiane Moreno,Melissa Nel,Evadnie Rampersaud,Jennifer Roggenbuck,Guy Rouleau,Bryan Traynor,Marka Van Blitterswijk,Wouter Van Rheenen,Jan Veldink,Jochen Weishaupt,Luke Drury,Matthew B Harms,Sali M K Farhan,Amyotrophic lateral sclerosis spectrum disorders Gene Curation Expert Panel
Source: Amyotrophic lateral sclerosis & frontotemporal degeneration
Objective: In 2021, the Clinical Genome Resource (ClinGen) amyotrophic lateral sclerosis (ALS) spectrum disorders Gene Curation Expert Panel (GCEP) was established to evaluate the strength of evidence for genes previously reported to be associated with ALS. Through this endeavor, we will provide standardized guidance to laboratories on which genes should be included in clinical genetic testing panels for ALS. In this manuscript, we aimed to assess the heterogeneity in the current global...
-
Friday, February 17, 2023
Author(s): Matteo Zanovello,Kristina Ibáñez,Anna-Leigh Brown,Prasanth Sivakumar,Alessandro Bombaci,Liana Santos,Joke J F A van Vugt,Giuseppe Narzisi,Ramita Karra,Sonja W Scholz,Jinhui Ding,J Raphael Gibbs,Adriano Chiò,Clifton Dalgard,Ben Weisburd,American Genome Center (TAGC) consortium, Genomics England Research Consortium, Project MinE ALS Sequencing Consortium, The NYGC ALS Consortium,Michael G Hanna,Linda Greensmith,Hemali Phatnani,Jan H Veldink,Bryan J Traynor,James Polke,Henry Houlden,Pietro Fratta,Arianna Tucci
Source: Brain : a journal of neurology
CAG repeat expansions in exon 1 of the AR gene on the X chromosome cause spinal and bulbar muscular atrophy, a male-specific progressive neuromuscular disorder associated with a variety of extra-neurological symptoms. The disease has a reported male prevalence of approximately 1:30 000 or less, but the AR repeat expansion frequency is unknown. We established a pipeline, which combines the use of the ExpansionHunter tool and visual validation, to detect AR CAG expansion on whole-genome sequencing...
-
Monday, January 23, 2023
Author(s): Meenakshi Sundaram Kumar,Karly M Stallworth,Anastasia C Murthy,Su Min Lim,Nan Li,Aastha Jain,James B Munro,Nicolas L Fawzi,Clotilde Lagier-Tourenne,Daryl A Bosco
Source: Journal of molecular biology
Deficient nucleocytoplasmic transport is emerging as a pathogenic feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including in ALS caused by mutations in Fused in Sarcoma (FUS). Recently, both wild-type and ALS-linked mutant FUS were shown to directly interact with the phenylalanine-glycine (FG)-rich nucleoporin 62 (Nup62) protein, where FUS WT/ Nup62 interactions were enriched within the nucleus but ALS-linked mutant FUS/ Nup62 interactions were enriched within...
-
Monday, January 09, 2023
Author(s): Heleen M Van't Spijker,Sandra Almeida
Source: Gene
A hexanucleotide repeat expansion in the C9ORF72 gene is the most common genetic alteration associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These neurodegenerative diseases share genetic, clinical and pathological features. The mutation in C9ORF72 appears to drive pathogenesis through a combination of loss of C9ORF72 normal function and gain of toxic effects due to the repeat expansion, which result in aggregation prone expanded RNAs and dipeptide repeat...
-
Monday, January 02, 2023
Author(s): Ahmad Al Khleifat,Alfredo Iacoangeli,Ashley R Jones,Joke J F A van Vugt,Matthieu Moisse,Aleksey Shatunov,Ramona A J Zwamborn,Rick A A van der Spek,Johnathan Cooper-Knock,Simon Topp,Wouter van Rheenen,Brendan Kenna,Kristel R Van Eijk,Kevin Kenna,Ross Byrne,Victoria López,Sarah Opie-Martin,Atay Vural,Yolanda Campos,Markus Weber,Bradley Smith,Isabella Fogh,Vincenzo Silani,Karen E Morrison,Richard Dobson,Michael A van Es,Russell L McLaughlin,Patrick Vourc'h,Adriano Chio,Philippe Corcia,Mamede de Carvalho,Marc Gotkine,Monica Povedano Panades,Jesus S Mora,Pamela J Shaw,John E Landers,Jonathan D Glass,Christopher E Shaw,Nazli Basak,Orla Hardiman,Wim Robberecht,Philip Van Damme,Leonard H van den Berg,Jan H Veldink,Ammar Al-Chalabi
Source: Frontiers in cellular neuroscience
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been...
-
Friday, December 23, 2022
Author(s): Meenakshi Sundaram Kumar,Megan E Fowler-Magaw,Daniel Kulick,Sivakumar Boopathy,Del Hayden Gadd,Melissa Rotunno,Catherine Douthwright,Diane Golebiowski,Issa Yusuf,Zuoshang Xu,Robert H Brown,Miguel Sena-Esteves,Alison L O'Neil,Daryl A Bosco
Source: International journal of molecular sciences
ALS-linked mutations induce aberrant conformations within the SOD1 protein that are thought to underlie the pathogenic mechanism of SOD1-mediated ALS. Although clinical trials are underway for gene silencing of SOD1, these approaches reduce both wild-type and mutated forms of SOD1. Here, we sought to develop anti-SOD1 nanobodies with selectivity for mutant and misfolded forms of human SOD1 over wild-type SOD1. Characterization of two anti-SOD1 nanobodies revealed that these biologics stabilize...
-
Friday, December 02, 2022
Author(s): Caroline B Pantazis,Andrian Yang,Erika Lara,Justin A McDonough,Cornelis Blauwendraat,Lirong Peng,Hideyuki Oguro,Jitendra Kanaujiya,ji*zhong Zou,David Sebesta,Gretchen Pratt,Erin Cross,Jeffrey Blockwick,Philip Buxton,Lauren Kinner-Bibeau,Constance Medura,Christopher Tompkins,Stephen Hughes,Marianita Santiana,Faraz fa*ghri,Mike A Nalls,Daniel Vitale,Shannon Ballard,Yue A Qi,Daniel M Ramos,Kailyn M Anderson,Julia Stadler,Priyanka Narayan,Jason Papademetriou,Luke Reilly,Matthew P Nelson,Sanya Aggarwal,Leah U Rosen,Peter Kirwan,Venkat Pisupati,Steven L Coon,Sonja W Scholz,Theresa Priebe,Miriam Öttl,Jian Dong,Marieke Meijer,Lara J M Janssen,Vanessa S Lourenco,Rik van der Kant,Dennis Crusius,Dominik Paquet,Ana-Caroline Raulin,Guojun Bu,Aaron Held,Brian J Wainger,Rebecca M C Gabriele,Jackie M Casey,Selina Wray,Dad Abu-Bonsrah,Clare L Parish,Melinda S Beccari,Don W Cleveland,Emmy Li,Indigo V L Rose,Martin Kampmann,Carles Calatayud Aristoy,Patrik Verstreken,Laurin Heinrich,Max Y Chen,Birgitt Schüle,Dan Dou,Erika L F Holzbaur,Maria Clara Zanellati,Richa Basundra,Mohanish Deshmukh,Sarah Cohen,Richa Khanna,Malavika Raman,Zachary S Nevin,Madeline Matia,Jonas Van Lent,Vincent Timmerman,Bruce R Conklin,Katherine Johnson Chase,Ke Zhang,Salome Funes,Daryl A Bosco,Lena Erlebach,Marc Welzer,Deborah Kronenberg-Versteeg,Guochang Lyu,Ernest Arenas,Elena Coccia,Lily Sarrafha,Tim Ahfeldt,John C Marioni,William C Skarnes,Mark R Cookson,Michael E Ward,Florian T Merkle
Source: Cell stem cell
Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including...
-
Sunday, November 13, 2022
Author(s): Sarah Opie-Martin,Alfredo Iacoangeli,Simon D Topp,Olubunmi Abel,Keith Mayl,Puja R Mehta,Aleksey Shatunov,Isabella Fogh,Harry Bowles,Naomi Limbachiya,Thomas P Spargo,Ahmad Al-Khleifat,Kelly L Williams,Jennifer Jockel-Balsarotti,Taha Bali,Wade Self,Lyndal Henden,Garth A Nicholson,Nicola Ticozzi,Diane McKenna-Yasek,Lu Tang,Pamela J Shaw,Adriano Chio,Albert Ludolph,Jochen H Weishaupt,John E Landers,Jonathan D Glass,Jesus S Mora,Wim Robberecht,Philip Van Damme,Russell McLaughlin,Orla Hardiman,Leonard van den Berg,Jan H Veldink,Phillippe Corcia,Zorica Stevic,Nailah Siddique,Vincenzo Silani,Ian P Blair,Dong-Sheng Fan,Florence Esselin,Elisa de la Cruz,William Camu,Nazli A Basak,Teepu Siddique,Timothy Miller,Robert H Brown,Ammar Al-Chalabi,Christopher E Shaw
Source: Nature communications
Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring...
-
Friday, October 21, 2022
Author(s): Katharina E Meijboom,Abbas Abdallah,Nicholas P Fordham,Hiroko Nagase,Tomás Rodriguez,Carolyn Kraus,Tania F Gendron,Gopinath Krishnan,Rustam Esanov,Nadja S Andrade,Matthew J Rybin,Melina Ramic,Zachary D Stephens,Alireza Edraki,Meghan T Blackwood,Aydan Kahriman,Nils Henninger,Jean-Pierre A Kocher,Michael Benatar,Michael H Brodsky,Leonard Petrucelli,Fen-Biao Gao,Erik J Sontheimer,Robert H Brown,Zane Zeier,Christian Mueller
Source: Nature communications
A GGGGCC(24+) hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), fatal neurodegenerative diseases with no cure or approved treatments that substantially slow disease progression or extend survival. Mechanistic underpinnings of neuronal death include C9ORF72 haploinsufficiency, sequestration of RNA-binding proteins in the nucleus, and production of dipeptide repeat proteins. Here, we...
-
Monday, September 26, 2022
Author(s): Puja R Mehta,Alfredo Iacoangeli,Sarah Opie-Martin,Joke J F A van Vugt,Ahmad Al Khleifat,Andrea Bredin,Lynn Ossher,Peter M Andersen,Orla Hardiman,Arpan R Mehta,Pietro Fratta,Kevin Talbot,Project MinE ALS Sequencing Consortium,Ammar Al-Chalabi
Source: Brain : a journal of neurology
Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative syndrome. In up to 20% of cases, a family history is observed. Although Mendelian disease gene variants are found in apparently sporadic ALS, genetic testing is usually restricted to those with a family history or younger patients with sporadic disease. With the advent of therapies targeting genetic ALS, it is important that everyone treatable is identified. We therefore sought to determine the probability of a clinically...
-
Thursday, May 19, 2022
Author(s): Gopinath Krishnan,Denitza Raitcheva,Daniel Bartlett,Mercedes Prudencio,Diane M McKenna-Yasek,Catherine Douthwright,Björn E Oskarsson,Shafeeq Ladha,Oliver D King,Sami J Barmada,Timothy M Miller,Robert Bowser,Jonathan K Watts,Leonard Petrucelli,Robert H Brown,Mark W Kankel,Fen-Biao Gao
Source: Nature communications
GGGGCC repeat expansion in C9ORF72, which can be translated in both sense and antisense directions into five dipeptide repeat (DPR) proteins, including poly(GP), poly(GR), and poly(GA), is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we developed sensitive assays that can detect poly(GA) and poly(GR) in the cerebrospinal fluid (CSF) of patients with C9ORF72 mutations. CSF poly(GA) and poly(GR) levels did not correlate with age at...
-
Monday, May 16, 2022
Author(s): Sabrina Paganoni,Suzanne Hendrix,Samuel P Dickson,Newman Knowlton,James D Berry,Michael A Elliott,Samuel Maiser,Chafic Karam,James B Caress,Margaret Ayo Owegi,Adam Quick,James Wymer,Stephen A Goutman,Daragh Heitzman,Terry D Heiman-Patterson,Carlayne Jackson,Colin Quinn,Jeffrey D Rothstein,Edward J Kasarskis,Jonathan Katz,Liberty Jenkins,Shafeeq S Ladha,Timothy M Miller,Stephen N Scelsa,Tuan H Vu,Christina Fournier,Kristin M Johnson,Andrea Swenson,Namita Goyal,Gary L Pattee,Suma Babu,Marianne Chase,Derek Dagostino,Meghan Hall,Gale Kittle,Mathew Eydinov,Joseph Ostrow,Lindsay Pothier,Rebecca Randall,Jeremy M Shefner,Alexander V Sherman,Eric Tustison,Prasha Vigneswaran,Hong Yu,Joshua Cohen,Justin Klee,Rudolph Tanzi,Walter Gilbert,Patrick Yeramian,Merit Cudkowicz
Source: Journal of neurology, neurosurgery, and psychiatry
CONCLUSIONS: Early PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.
-
Wednesday, April 06, 2022
Author(s): Desiree M Baron,Adam R Fenton,Sara Saez-Atienzar,Anthony Giampetruzzi,Aparna Sreeram,None Shankaracharya,Pamela J Keagle,Victoria R Doocy,Nathan J Smith,Eric W Danielson,Megan Andresano,Mary C McCormack,Jaqueline Garcia,Valérie Bercier,Ludo Van Den Bosch,Jonathan R Brent,Claudia Fallini,Bryan J Traynor,Erika L F Holzbaur,John E Landers
Source: Cell reports
Understanding the pathogenic mechanisms of disease mutations is critical to advancing treatments. ALS-associated mutations in the gene encoding the microtubule motor KIF5A result in skipping of exon 27 (KIF5A^(ΔExon27)) and the encoding of a protein with a novel 39 amino acid residue C-terminal sequence. Here, we report that expression of ALS-linked mutant KIF5A results in dysregulated motor activity, cellular mislocalization, altered axonal transport, and decreased neuronal survival....
-
Friday, April 01, 2022
Author(s): Chen Eitan,Aviad Siany,Elad Barkan,Tsviya Olender,Kristel R van Eijk,Matthieu Moisse,Sali M K Farhan,Yehuda M Danino,Eran Yanowski,Hagai Marmor-Kollet,Natalia Rivkin,Nancy Sarah Yacovzada,Shu-Ting Hung,Johnathan Cooper-Knock,Chien-Hsiung Yu,Cynthia Louis,Seth L Masters,Kevin P Kenna,Rick A A van der Spek,William Sproviero,Ahmad Al Khleifat,Alfredo Iacoangeli,Aleksey Shatunov,Ashley R Jones,Yael Elbaz-Alon,Yahel Cohen,Elik Chapnik,Daphna Rothschild,Omer Weissbrod,Gilad Beck,Elena Ainbinder,Shifra Ben-Dor,Sebastian Werneburg,Dorothy P Schafer,Robert H Brown,Pamela J Shaw,Philip Van Damme,Leonard H van den Berg,Hemali Phatnani,Eran Segal,Justin K Ichida,Ammar Al-Chalabi,Jan H Veldink,Project MinE ALS Sequencing Consortium,NYGC ALS Consortium,Eran Hornstein
Source: Nature neuroscience
The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies. Here, we performed region-based rare variant association analysis of 25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS controls. We identified interleukin-18 receptor accessory protein (IL18RAP) 3' untranslated region (3'UTR) variants as significantly enriched in...
-
Friday, March 11, 2022
Author(s): Cristian Arredondo,Carolina Cefaliello,Agnieszka Dyrda,Nur Jury,Pablo Martinez,Iván Díaz,Armando Amaro,Helene Tran,Danna Morales,Maria Pertusa,Lorelei Stoica,Elsa Fritz,Daniela Corvalán,Sebastián Abarzúa,Maxs Méndez-Ruette,Paola Fernández,Fabiola Rojas,Meenakshi Sundaram Kumar,Rodrigo Aguilar,Sandra Almeida,Alexandra Weiss,Fernando J Bustos,Fernando González-Nilo,Carolina Otero,Maria Florencia Tevy,Daryl A Bosco,Juan C Sáez,Thilo Kähne,Fen-Biao Gao,James D Berry,Katharine Nicholson,Miguel Sena-Esteves,Rodolfo Madrid,Diego Varela,Martin Montecino,Robert H Brown,Brigitte van Zundert
Source: Neuron
Non-cell-autonomous mechanisms contribute to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), in which astrocytes release unidentified factors that are toxic to motoneurons (MNs). We report here that mouse and patient iPSC-derived astrocytes with diverse ALS/FTD-linked mutations (SOD1, TARDBP, and C9ORF72) display elevated levels of intracellular inorganic polyphosphate (polyP), a ubiquitous, negatively charged biopolymer. PolyP levels are...
-
Wednesday, February 23, 2022
Author(s): Paul J Hop,Ramona A J Zwamborn,Eilis Hannon,Gemma L Shireby,Marta F Nabais,Emma M Walker,Wouter van Rheenen,Joke J F A van Vugt,Annelot M Dekker,Henk-Jan Westeneng,Gijs H P Tazelaar,Kristel R van Eijk,Matthieu Moisse,Denis Baird,Ahmad Al Khleifat,Alfredo Iacoangeli,Nicola Ticozzi,Antonia Ratti,Jonathan Cooper-Knock,Karen E Morrison,Pamela J Shaw,A Nazli Basak,Adriano Chiò,Andrea Calvo,Cristina Moglia,Antonio Canosa,Maura Brunetti,Maurizio Grassano,Marc Gotkine,Yossef Lerner,Michal Zabari,Patrick Vourc'h,Philippe Corcia,Philippe Couratier,Jesus S Mora Pardina,Teresa Salas,Patrick Dion,Jay P Ross,Robert D Henderson,Susan Mathers,Pamela A McCombe,Merrilee Needham,Garth Nicholson,Dominic B Rowe,Roger Pamphlett,Karen A Mather,Perminder S Sachdev,Sarah Furlong,Fleur C Garton,Anjali K Henders,Tian Lin,Shyuan T Ngo,Frederik J Steyn,Leanne Wallace,Kelly L Williams,BIOS Consortium,Brain MEND Consortium,Miguel Mitne Neto,Ruben J Cauchi,Ian P Blair,Matthew C Kiernan,Vivian Drory,Monica Povedano,Mamede de Carvalho,Susana Pinto,Markus Weber,Guy A Rouleau,Vincenzo Silani,John E Landers,Christopher E Shaw,Peter M Andersen,Allan F McRae,Michael A van Es,R Jeroen Pasterkamp,Naomi R Wray,Russell L McLaughlin,Orla Hardiman,Kevin P Kenna,Ellen Tsai,Heiko Runz,Ammar Al-Chalabi,Leonard H van den Berg,Philip Van Damme,Jonathan Mill,Jan H Veldink
Source: Science translational medicine
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45...
-
Friday, February 18, 2022
Author(s): Pin-Tsun Justin Lee,Zachary Kennedy,Yuzhen Wang,Yimeng Lu,Carolina Cefaliello,Özgün Uyan,Chun-Qing Song,Bruno Miguel da Cruz Godinho,Zuoshang Xu,Mary Rusckowski,Wen Xue,Robert H Brown
Source: Annals of neurology
OBJECTIVE: The objective of this study is to develop a novel method for monitoring the integrity of motor neurons in vivo by quantifying net retrograde axonal transport.
-
Tuesday, February 01, 2022
Author(s): Wouter van Rheenen,Rick A A van der Spek,Mark K Bakker,Joke J F A van Vugt,Paul J Hop,Ramona A J Zwamborn,Niek de Klein,Harm-Jan Westra,Olivier B Bakker,Patrick Deelen,Gemma Shireby,Eilis Hannon,Matthieu Moisse,Denis Baird,Restuadi Restuadi,Egor Dolzhenko,Annelot M Dekker,Klara Gawor,Henk-Jan Westeneng,Gijs H P Tazelaar,Kristel R van Eijk,Maarten Kooyman,Ross P Byrne,Mark Doherty,Mark Heverin,Ahmad Al Khleifat,Alfredo Iacoangeli,Aleksey Shatunov,Nicola Ticozzi,Johnathan Cooper-Knock,Bradley N Smith,Marta Gromicho,Siddharthan Chandran,Suvankar Pal,Karen E Morrison,Pamela J Shaw,John Hardy,Richard W Orrell,Michael Sendtner,Thomas Meyer,Nazli Başak,Anneke J van der Kooi,Antonia Ratti,Isabella Fogh,Cinzia Gellera,Giuseppe Lauria,Stefania Corti,Cristina Cereda,Daisy Sproviero,Sandra D'Alfonso,Gianni Sorarù,Gabriele Siciliano,Massimiliano Filosto,Alessandro Padovani,Adriano Chiò,Andrea Calvo,Cristina Moglia,Maura Brunetti,Antonio Canosa,Maurizio Grassano,Ettore Beghi,Elisabetta Pupillo,Giancarlo Logroscino,Beatrice Nefussy,Alma Osmanovic,Angelica Nordin,Yossef Lerner,Michal Zabari,Marc Gotkine,Robert H Baloh,Shaughn Bell,Patrick Vourc'h,Philippe Corcia,Philippe Couratier,Stéphanie Millecamps,Vincent Meininger,François Salachas,Jesus S Mora Pardina,Abdelilah Assialioui,Ricardo Rojas-García,Patrick A Dion,Jay P Ross,Albert C Ludolph,Jochen H Weishaupt,David Brenner,Axel Freischmidt,Gilbert Bensimon,Alexis Brice,Alexandra Durr,Christine A M Payan,Safa Saker-Delye,Nicholas W Wood,Simon Topp,Rosa Rademakers,Lukas Tittmann,Wolfgang Lieb,Andre Franke,Stephan Ripke,Alice Braun,Julia Kraft,David C Whiteman,Catherine M Olsen,Andre G Uitterlinden,Albert Hofman,Marcella Rietschel,Sven Cichon,Markus M Nöthen,Philippe Amouyel,SLALOM Consortium,PARALS Consortium,SLAGEN Consortium,SLAP Consortium,Bryan J Traynor,Andrew B Singleton,Miguel Mitne Neto,Ruben J Cauchi,Roel A Ophoff,Martina Wiedau-Pazos,Catherine Lomen-ho*rth,Vivianna M van Deerlin,Julian Grosskreutz,Annekathrin Roediger,Nayana Gaur,Alexander Jörk,Tabea Barthel,Erik Theele,Benjamin Ilse,Beatrice Stubendorff,Otto W Witte,Robert Steinbach,Christian A Hübner,Caroline Graff,Lev Brylev,Vera Fominykh,Vera Demeshonok,Anastasia Ataulina,Boris Rogelj,Blaž Koritnik,Janez Zidar,Metka Ravnik-Glavač,Damjan Glavač,Zorica Stević,Vivian Drory,Monica Povedano,Ian P Blair,Matthew C Kiernan,Beben Benyamin,Robert D Henderson,Sarah Furlong,Susan Mathers,Pamela A McCombe,Merrilee Needham,Shyuan T Ngo,Garth A Nicholson,Roger Pamphlett,Dominic B Rowe,Frederik J Steyn,Kelly L Williams,Karen A Mather,Perminder S Sachdev,Anjali K Henders,Leanne Wallace,Mamede de Carvalho,Susana Pinto,Susanne Petri,Markus Weber,Guy A Rouleau,Vincenzo Silani,Charles J Curtis,Gerome Breen,Jonathan D Glass,Robert H Brown,John E Landers,Christopher E Shaw,Peter M Andersen,Ewout J N Groen,Michael A van Es,R Jeroen Pasterkamp,Dongsheng Fan,Fleur C Garton,Allan F McRae,George Davey Smith,Tom R Gaunt,Michael A Eberle,Jonathan Mill,Russell L McLaughlin,Orla Hardiman,Kevin P Kenna,Naomi R Wray,Ellen Tsai,Heiko Runz,Lude Franke,Ammar Al-Chalabi,Philip Van Damme,Leonard H van den Berg,Jan H Veldink
Source: Nature genetics
No abstract
-
Saturday, January 29, 2022
Author(s): Ahmad Al Khleifat,Alfredo Iacoangeli,Joke J F A van Vugt,Harry Bowles,Matthieu Moisse,Ramona A J Zwamborn,Rick A A van der Spek,Aleksey Shatunov,Johnathan Cooper-Knock,Simon Topp,Ross Byrne,Cinzia Gellera,Victoria López,Ashley R Jones,Sarah Opie-Martin,Atay Vural,Yolanda Campos,Wouter van Rheenen,Brendan Kenna,Kristel R Van Eijk,Kevin Kenna,Markus Weber,Bradley Smith,Isabella Fogh,Vincenzo Silani,Karen E Morrison,Richard Dobson,Michael A van Es,Russell L McLaughlin,Patrick Vourc'h,Adriano Chio,Philippe Corcia,Mamede de Carvalho,Marc Gotkine,Monica P Panades,Jesus S Mora,Pamela J Shaw,John E Landers,Jonathan D Glass,Christopher E Shaw,Nazli Basak,Orla Hardiman,Wim Robberecht,Philip Van Damme,Leonard H van den Berg,Jan H Veldink,Ammar Al-Chalabi
Source: NPJ genomic medicine
There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype....
-
Wednesday, January 19, 2022
Author(s): Sai Zhang,Johnathan Cooper-Knock,Annika K Weimer,Minyi Shi,Tobias Moll,Jack N G Marshall,Calum Harvey,Helia Ghahremani Nezhad,John Franklin,Cleide Dos Santos Souza,Ke Ning,Cheng Wang,Jingjing Li,Allison A Dilliott,Sali Farhan,Eran Elhaik,Iris Pasniceanu,Matthew R Livesey,Chen Eitan,Eran Hornstein,Kevin P Kenna,Project MinE ALS Sequencing Consortium,Jan H Veldink,Laura Ferraiuolo,Pamela J Shaw,Michael P Snyder
Source: Neuron
Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated...
-
Friday, December 24, 2021
Author(s): Hélène Tran,Michael P Moazami,Huiya Yang,Diane McKenna-Yasek,Catherine L Douthwright,Courtney Pinto,Jake Metterville,Minwook Shin,Nitasha Sanil,Craig Dooley,Ajit Puri,Alexandra Weiss,Nicholas Wightman,Heather Gray-Edwards,Miklos Marosfoi,Robert M King,Thomas Kenderdine,Daniele Fabris,Robert Bowser,Jonathan K Watts,Robert H Brown
Source: Nature medicine
Expansions of a G(4)C(2) repeat in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating adult-onset neurodegenerative disorders. Using C9-ALS/FTD patient-derived cells and C9ORF72 BAC transgenic mice, we generated and optimized antisense oligonucleotides (ASOs) that selectively blunt expression of G(4)C(2) repeat-containing transcripts and effectively suppress tissue levels of poly(GP) dipeptides. ASOs with...
-
Wednesday, December 22, 2021
Author(s): Sabrina Paganoni,James D Berry,Melanie Quintana,Eric Macklin,Benjamin R Saville,Michelle A Detry,Marianne Chase,Alexander V Sherman,Hong Yu,Kristin Drake,Jinsy Andrews,Jeremy Shefner,Lori B Chibnik,Matteo Vestrucci,Merit E Cudkowicz,Healey ALS Platform Trial Study Group
Source: Annals of neurology
Current therapeutic development in amyotrophic lateral sclerosis (ALS) relies on individual randomized clinical trials to test a specific investigational product in a single patient population. This approach has intrinsic limitations, including cost, time, and lack of flexibility. Adaptive platform trials represent a novel approach to investigate several interventions for a single disease in a continuous manner. Already in use in oncology, this approach is now being employed more often in...
-
Friday, December 10, 2021
Author(s): Merit E Cudkowicz,Stacy R Lindborg,Namita A Goyal,Robert G Miller,Matthew J Burford,James D Berry,Katharine A Nicholson,Tahseen Mozaffar,Jonathan S Katz,Liberty J Jenkins,Robert H Baloh,Richard A Lewis,Nathan P Staff,Margaret A Owegi,Donald A Berry,Yael Gothelf,Yossef S Levy,Revital Aricha,Ralph Z Kern,Anthony J Windebank,Robert H Brown
Source: Muscle & nerve
INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression.
-
Tuesday, December 07, 2021
Author(s): Wouter van Rheenen,Rick A A van der Spek,Mark K Bakker,Joke J F A van Vugt,Paul J Hop,Ramona A J Zwamborn,Niek de Klein,Harm-Jan Westra,Olivier B Bakker,Patrick Deelen,Gemma Shireby,Eilis Hannon,Matthieu Moisse,Denis Baird,Restuadi Restuadi,Egor Dolzhenko,Annelot M Dekker,Klara Gawor,Henk-Jan Westeneng,Gijs H P Tazelaar,Kristel R van Eijk,Maarten Kooyman,Ross P Byrne,Mark Doherty,Mark Heverin,Ahmad Al Khleifat,Alfredo Iacoangeli,Aleksey Shatunov,Nicola Ticozzi,Johnathan Cooper-Knock,Bradley N Smith,Marta Gromicho,Siddharthan Chandran,Suvankar Pal,Karen E Morrison,Pamela J Shaw,John Hardy,Richard W Orrell,Michael Sendtner,Thomas Meyer,Nazli Başak,Anneke J van der Kooi,Antonia Ratti,Isabella Fogh,Cinzia Gellera,Giuseppe Lauria,Stefania Corti,Cristina Cereda,Daisy Sproviero,Sandra D'Alfonso,Gianni Sorarù,Gabriele Siciliano,Massimiliano Filosto,Alessandro Padovani,Adriano Chiò,Andrea Calvo,Cristina Moglia,Maura Brunetti,Antonio Canosa,Maurizio Grassano,Ettore Beghi,Elisabetta Pupillo,Giancarlo Logroscino,Beatrice Nefussy,Alma Osmanovic,Angelica Nordin,Yossef Lerner,Michal Zabari,Marc Gotkine,Robert H Baloh,Shaughn Bell,Patrick Vourc'h,Philippe Corcia,Philippe Couratier,Stéphanie Millecamps,Vincent Meininger,François Salachas,Jesus S Mora Pardina,Abdelilah Assialioui,Ricardo Rojas-García,Patrick A Dion,Jay P Ross,Albert C Ludolph,Jochen H Weishaupt,David Brenner,Axel Freischmidt,Gilbert Bensimon,Alexis Brice,Alexandra Durr,Christine A M Payan,Safa Saker-Delye,Nicholas W Wood,Simon Topp,Rosa Rademakers,Lukas Tittmann,Wolfgang Lieb,Andre Franke,Stephan Ripke,Alice Braun,Julia Kraft,David C Whiteman,Catherine M Olsen,Andre G Uitterlinden,Albert Hofman,Marcella Rietschel,Sven Cichon,Markus M Nöthen,Philippe Amouyel,SLALOM Consortium,PARALS Consortium,SLAGEN Consortium,SLAP Consortium,Bryan J Traynor,Andrew B Singleton,Miguel Mitne Neto,Ruben J Cauchi,Roel A Ophoff,Martina Wiedau-Pazos,Catherine Lomen-ho*rth,Vivianna M van Deerlin,Julian Grosskreutz,Annekathrin Roediger,Nayana Gaur,Alexander Jörk,Tabea Barthel,Erik Theele,Benjamin Ilse,Beatrice Stubendorff,Otto W Witte,Robert Steinbach,Christian A Hübner,Caroline Graff,Lev Brylev,Vera Fominykh,Vera Demeshonok,Anastasia Ataulina,Boris Rogelj,Blaž Koritnik,Janez Zidar,Metka Ravnik-Glavač,Damjan Glavač,Zorica Stević,Vivian Drory,Monica Povedano,Ian P Blair,Matthew C Kiernan,Beben Benyamin,Robert D Henderson,Sarah Furlong,Susan Mathers,Pamela A McCombe,Merrilee Needham,Shyuan T Ngo,Garth A Nicholson,Roger Pamphlett,Dominic B Rowe,Frederik J Steyn,Kelly L Williams,Karen A Mather,Perminder S Sachdev,Anjali K Henders,Leanne Wallace,Mamede de Carvalho,Susana Pinto,Susanne Petri,Markus Weber,Guy A Rouleau,Vincenzo Silani,Charles J Curtis,Gerome Breen,Jonathan D Glass,Robert H Brown,John E Landers,Christopher E Shaw,Peter M Andersen,Ewout J N Groen,Michael A van Es,R Jeroen Pasterkamp,Dongsheng Fan,Fleur C Garton,Allan F McRae,George Davey Smith,Tom R Gaunt,Michael A Eberle,Jonathan Mill,Russell L McLaughlin,Orla Hardiman,Kevin P Kenna,Naomi R Wray,Ellen Tsai,Heiko Runz,Lude Franke,Ammar Al-Chalabi,Philip Van Damme,Leonard H van den Berg,Jan H Veldink
Source: Nature genetics
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset...
-
Wednesday, December 01, 2021
Author(s): Heleen M van 't Spijker,Emily E Stackpole,Sandra Almeida,Olga Katsara,Botao Liu,Kuang Shen,Robert J Schneider,Fen-Biao Gao,Joel D Richter
Source: RNA (New York, N.Y.)
GGGGCC (G(4)C(2)) repeat expansion in the first intron of C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia. Repeat-containing RNA is translated into dipeptide repeat (DPR) proteins, some of which are neurotoxic. Using dynamic ribosome profiling, we identified three translation initiation sites in the intron upstream of (G(4)C(2)) repeats; these sites are detected irrespective of the presence or absence of the repeats. During translocation, ribosomes appear to be stalled...
-
Monday, August 30, 2021
Author(s): Janel O Johnson,Ruth Chia,Danny E Miller,Rachel Li,Ravindran Kumaran,Yevgeniya Abramzon,Nada Alahmady,Alan E Renton,Simon D Topp,J Raphael Gibbs,Mark R Cookson,Marya S Sabir,Clifton L Dalgard,Claire Troakes,Ashley R Jones,Aleksey Shatunov,Alfredo Iacoangeli,Ahmad Al Khleifat,Nicola Ticozzi,Vincenzo Silani,Cinzia Gellera,Ian P Blair,Carol Dobson-Stone,John B Kwok,Emily S Bonkowski,Robin Palvadeau,Pentti J Tienari,Karen E Morrison,Pamela J Shaw,Ammar Al-Chalabi,Robert H Brown,Andrea Calvo,Gabriele Mora,Hind Al-Saif,Marc Gotkine,Fawn Leigh,Irene J Chang,Seth J Perlman,Ian Glass,Anna I Scott,Christopher E Shaw,A Nazli Basak,John E Landers,Adriano Chiò,Thomas O Crawford,Bradley N Smith,Bryan J Traynor,FALS Sequencing Consortium; American Genome Center; International ALS Genomics Consortium; and ITALSGEN Consortium,Bradley N Smith,Nicola Ticozzi,Claudia Fallini,Athina Soragia Gkazi,Simon D Topp,Emma L Scotter,Kevin P Kenna,Pamela Keagle,Cinzia Tiloca,Caroline Vance,Claire Troakes,Claudia Colombrita,Andrew King,Viviana Pensato,Barbara Castellotti,Frank Baas,Anneloor L M A Ten Asbroek,Diane McKenna-Yasek,Russell L McLaughlin,Meraida Polak,Seneshaw Asress,Jesús Esteban-Pérez,Zorica Stevic,Sandra D'Alfonso,Letizia Mazzini,Giacomo P Comi,Roberto Del Bo,Mauro Ceroni,Stella Gagliardi,Giorgia Querin,Cinzia Bertolin,Wouter van Rheenen,Rosa Rademakers,Marka van Blitterswijk,Giuseppe Lauria,Stefano Duga,Stefania Corti,Cristina Cereda,Lucia Corrado,Gianni Sorarù,Kelly L Williams,Garth A Nicholson,Ian P Blair,Claire Leblond-Manry,Guy A Rouleau,Orla Hardiman,Karen E Morrison,Jan H Veldink,Leonard H van den Berg,Ammar Al-Chalabi,Hardev Pall,Pamela J Shaw,Martin R Turner,Kevin Talbot,Franco Taroni,Alberto García-Redondo,Zheyang Wu,Jonathan D Glass,Cinzia Gellera,Antonia Ratti,Robert H Brown,Vincenzo Silani,Christopher E Shaw,John E Landers,Clifton L Dalgard,Adelani Adeleye,Anthony R Soltis,Camille Alba,Coralie Viollet,Dagmar Bacikova,Daniel N Hupalo,Gauthaman Sukumar,Harvey B Pollard,Matthew D Wilkerson,Elisa McGrath Martinez,Yevgeniya Abramzon,Sarah Ahmed,Sampath Arepalli,Robert H Baloh,Robert Bowser,Christopher B Brady,Alexis Brice,James Broach,Roy H Campbell,William Camu,Ruth Chia,John Cooper-Knock,Jinhui Ding,Carsten Drepper,Vivian E Drory,Travis L Dunckley,John D Eicher,Bryce K England,Faraz fa*ghri,Eva Feldman,Mary Kay Floeter,Pietro Fratta,Joshua T Geiger,Glenn Gerhard,J Raphael Gibbs,Summer B Gibson,Jonathan D Glass,John Hardy,Matthew B Harms,Terry D Heiman-Patterson,Dena G Hernandez,Lilja Jansson,Janine Kirby,Neil W Kowall,Hannu Laaksovirta,Natalie Landeck,Francesco Landi,Isabelle Le Ber,Serge Lumbroso,Daniel J L MacGowan,Nicholas J Maragakis,Gabriele Mora,Kevin Mouzat,Natalie A Murphy,Liisa Myllykangas,Mike A Nalls,Richard W Orrell,Lyle W Ostrow,Roger Pamphlett,Stuart Pickering-Brown,Erik P Pioro,Olga Pletnikova,Hannah A Pliner,Stefan M Pulst,John M Ravits,Alan E Renton,Alberto Rivera,Wim Robberecht,Ekaterina Rogaeva,Sara Rollinson,Jeffrey D Rothstein,Sonja W Scholz,Michael Sendtner,Pamela J Shaw,Katie C Sidle,Zachary Simmons,Andrew B Singleton,Nathan Smith,David J Stone,Pentti J Tienari,Juan C Troncoso,Miko Valori,Philip Van Damme,Vivianna M Van Deerlin,Ludo Van Den Bosch,Lorne Zinman,John E Landers,Adriano Chiò,Bryan J Traynor,Stefania M Angelocola,Francesco P Ausiello,Marco Barberis,Ilaria Bartolomei,Stefania Battistini,Enrica Bersano,Giulia Bisogni,Giuseppe Borghero,Maura Brunetti,Corrado Cabona,Andrea Calvo,Fabrizio Canale,Antonio Canosa,Teresa A Cantisani,Margherita Capasso,Claudia Caponnetto,Patrizio Cardinali,Paola Carrera,Federico Casale,Adriano Chiò,Tiziana Colletti,Francesca L Conforti,Amelia Conte,Elisa Conti,Massimo Corbo,Stefania Cuccu,Eleonora Dalla Bella,Eustachio D'Errico,Giovanni DeMarco,Raffaele Dubbioso,Carlo Ferrarese,Pilar M Ferraro,Massimo Filippi,Nicola Fini,Gianluca Floris,Giuseppe Fuda,Salvatore Gallone,Giulia Gianferrari,Fabio Giannini,Maurizio Grassano,Lucia Greco,Barbara Iazzolino,Alessandro Introna,Vincenzo La Bella,Serena Lattante,Giuseppe Lauria,Rocco Liguori,Giancarlo Logroscino,Francesco O Logullo,Christian Lunetta,Paola Mandich,Jessica Mandrioli,Umberto Manera,Fiore Manganelli,Giuseppe Marangi,Kalliopi Marinou,Maria Giovanna Marrosu,Ilaria Martinelli,Sonia Messina,Cristina Moglia,Gabriele Mora,Lorena Mosca,Maria R Murru,Paola Origone,Carla Passaniti,Cristina Petrelli,Antonio Petrucci,Susanna Pozzi,Maura Pugliatti,Angelo Quattrini,Claudia Ricci,Giulia Riolo,Nilo Riva,Massimo Russo,Mario Sabatelli,Paolina Salamone,Marco Salivetto,Fabrizio Salvi,Marialuisa Santarelli,Luca Sbaiz,Riccardo Sideri,Isabella Simone,Cecilia Simonini,Rossella Spataro,Raffaella Tanel,Gioacchino Tedeschi,Anna Ticca,Antonella Torriello,Stefania Tranquilli,Lucio Tremolizzo,Francesca Trojsi,Rosario Vasta,Veria Vacchiano,Giuseppe Vita,Paolo Volanti,Marcella Zollino,Elisabetta Zucchi
Source: JAMA neurology
CONCLUSIONS AND RELEVANCE: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
-
Thursday, August 05, 2021
Author(s): Colin Quinn,Corey T Mcmillan,Margaret A Owegi,Kelly Almasy,Catherine Douthwright,Diane Mckenna-Yasek,Namita A Goyal,James Berry,Robert H Brown
Source: Amyotrophic lateral sclerosis & frontotemporal degeneration
Objective: To measure the correlation between single breath counting (SBC) and forced vital capacity (liters, FVC(L)) in amyotrophic lateral sclerosis (ALS) patients and to define the utility of SBC for determining when patients meet the threshold for initiation of noninvasive positive pressure ventilation (FVC
-
Friday, June 25, 2021
Author(s): Merel O Mol,Tsz H Wong,Shamiram Melhem,Sreya Basu,Riccardo Viscusi,Niels Galjart,Annemieke J M Rozemuller,Claudia Fallini,John E Landers,Laura Donker Kaat,Harro Seelaar,Jeroen G J van Rooij,John C van Swieten
Source: Neurology. Genetics
CONCLUSIONS: Our findings support the role of TUBA4A variants as rare genetic cause of familial FTD.
-
Tuesday, June 22, 2021
Author(s): Alexa Lampasona,Sandra Almeida,Fen-Biao Gao
Source: Neurobiology of aging
GGGGCC (G(4)C(2)) repeat expansion in the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, two devastating age-dependent neurodegenerative disorders. Both sense and antisense repeat RNAs can be translated into 5 different dipeptide repeat proteins, such as poly(GR), which is toxic in various cellular and animal models. However, it remains unknown how poly(GR) is synthesized in patient neurons. Using a reporter construct...
-
Thursday, June 03, 2021
Author(s): Yubing Lu,Sandra Almeida,Fen-Biao Gao
Source: Acta neuropathologica
No abstract
-
Wednesday, June 02, 2021
Author(s): Eric J Schmidt,Salome Funes,Jeanne E McKeon,Brittany R Morgan,Sivakumar Boopathy,Lauren C O'Connor,Osman Bilsel,Francesca Massi,Antoine Jégou,Daryl A Bosco
Source: Proceedings of the National Academy of Sciences of the United States of America
Profilin-1 (PFN1) plays important roles in modulating actin dynamics through binding both monomeric actin and proteins enriched with polyproline motifs. Mutations in PFN1 have been linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). However, whether ALS-linked mutations affect PFN1 function has remained unclear. To address this question, we employed an unbiased proteomics analysis in mammalian cells to identify proteins that differentially interact with mutant and...
-
Tuesday, June 01, 2021
Author(s): Yen-Chen Lin,Meenakshi Sundaram Kumar,Nandini Ramesh,Eric N Anderson,Aivi T Nguyen,Boram Kim,Simon Cheung,Justin A McDonough,William C Skarnes,Rodrigo Lopez-Gonzalez,John E Landers,Nicolas L Fawzi,Ian R A Mackenzie,Edward B Lee,Jeffrey A Nickerson,David Grunwald,Udai B Pandey,Daryl A Bosco
Source: Nature neuroscience
Nucleocytoplasmic transport (NCT) decline occurs with aging and neurodegeneration. Here, we investigated the NCT pathway in models of amyotrophic lateral sclerosis-fused in sarcoma (ALS-FUS). Expression of ALS-FUS led to a reduction in NCT and nucleoporin (Nup) density within the nuclear membrane of human neurons. FUS and Nups were found to interact independently of RNA in cells and to alter the phase-separation properties of each other in vitro. FUS-Nup interactions were not localized to...
-
Wednesday, March 17, 2021
Author(s): Esteban Quezada,Claudio Cappelli,Iván Diaz,Nur Jury,Nicholas Wightman,Robert H Brown,Martín Montecino,Brigitte van Zundert
Source: Clinical epigenetics
CONCLUSIONS: Our findings place BET bromodomain inhibitors as a potential therapy for C9ALS/FTD by ameliorating C9ORF72-associated pathological and behavioral abnormalities. Our finding that PFI-1 increases accumulation of intranuclear RNA foci is in agreement with recent data in flies suggesting that nuclear RNA foci can be neuroprotective by sequestering repeat transcripts that result in toxic DPRs.
-
Tuesday, February 16, 2021
Author(s): Stephanie R Shepheard,Matthew D Parker,Johnathan Cooper-Knock,Nick S Verber,Lee Tuddenham,Paul Heath,Nick Beauchamp,Elsie Place,Elizabeth S A Sollars,Martin R Turner,Andrea Malaspina,Pietro Fratta,Channa Hewamadduma,Thomas M Jenkins,Christopher J McDermott,Dennis Wang,Janine Kirby,Pamela J Shaw,Project MINE Consortium,Project MinE
Source: Journal of neurology, neurosurgery, and psychiatry
CONCLUSIONS: Routine screening for ALS-associated pathogenic mutations in a specialised ALS referral clinic will impact clinical care in 21% of cases. An additional 21% of patients have variants in the ALS gene panel currently of unconfirmed significance after removing non-specific or predicted benign variants. Overall, variants within known ALS-linked genes are of potential clinical importance in 42% of patients.
-
Tuesday, February 09, 2021
Author(s): Yuanjing Liu,Jean-Cosme Dodart,Helene Tran,Shaunna Berkovitch,Maurine Braun,Michael Byrne,Ann F Durbin,Xiao Shelley Hu,Naoki Iwamoto,Hyun Gyung Jang,Pachamuthu Kandasamy,Fangjun Liu,Kenneth Longo,Jörg Ruschel,Juili Shelke,Hailin Yang,Yuan Yin,Amy Donner,Zhong Zhong,Chandra Vargeese,Robert H Brown
Source: Nature communications
A large G(4)C(2)-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal degeneration associated with this expansion arises from a loss of C9orf72 protein, the accumulation of RNA foci, the expression of dipeptide repeat (DPR) proteins, or all these factors. We report the discovery of a new targeting sequence that is common to all C9orf72 transcripts but enables preferential knockdown of repeat-containing...
-
Tuesday, February 02, 2021
Author(s): Mehdi Ghasemi,Kiandokht Keyhanian,Catherine Douthwright
Source: Cells
Since the discovery of the chromosome 9 open reading frame 72 (C9orf72) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) and frontotemporal dementia (FTD), progress in understanding the signaling pathways related to this mutation can only be described as intriguing. Two major theories have been suggested-(i) loss of function or haploinsufficiency and (ii) toxic gain of function from either C9orf72...
-
Monday, February 01, 2021
Author(s): Sara Saez-Atienzar,Sara Bandres-Ciga,Rebekah G Langston,Jonggeol J Kim,Shing Wan Choi,Regina H Reynolds,International ALS Genomics Consortium,ITALSGEN,Yevgeniya Abramzon,Ramita Dewan,Sarah Ahmed,John E Landers,Ruth Chia,Mina Ryten,Mark R Cookson,Michael A Nalls,Adriano Chiò,Bryan J Traynor
Source: Science advances
Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection...
-
Sunday, January 03, 2021
Author(s): Matthieu Moisse,Ramona A J Zwamborn,Joke van Vugt,Rick van der Spek,Wouter van Rheenen,Brendan Kenna,Kristel Van Eijk,Kevin Kenna,Philippe Corcia,Philippe Couratier,Patrick Vourc'h,Orla Hardiman,Russell McLaughin,Marc Gotkine,Vivian Drory,Nicola Ticozzi,Vincenzo Silani,Mamede de Carvalho,Jesús S Mora Pardina,Monica Povedano,Peter M Andersen,Markus Weber,Nazli A Başak,Xiao Chen,Michael A Eberle,Ammar Al-Chalabi,Chris Shaw,Pamela J Shaw,Karen E Morrison,John E Landers,Jonathan D Glass,Wim Robberecht,Michael van Es,Leonard van den Berg,Jan Veldink,Philip Van Damme,Project MinE Sequencing Consortium
Source: Annals of neurology
OBJECTIVE: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency.
-
Wednesday, December 02, 2020
Author(s): Johnathan Cooper-Knock,Sai Zhang,Kevin P Kenna,Tobias Moll,John P Franklin,Samantha Allen,Helia Ghahremani Nezhad,Alfredo Iacoangeli,Nancy Y Yacovzada,Chen Eitan,Eran Hornstein,Eran Elhaik,Petra Celadova,Daniel Bose,Sali Farhan,Simon Fishilevich,Doron Lancet,Karen E Morrison,Christopher E Shaw,Ammar Al-Chalabi,Project MinE ALS Sequencing Consortium,Jan H Veldink,Janine Kirby,Michael P Snyder,Pamela J Shaw
Source: Cell reports
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding genome, but further characterization has been limited by lack of appropriate tools. By designing and applying a pipeline to identify pathogenic genetic...
-
Thursday, November 26, 2020
Author(s): Ramita Dewan,Ruth Chia,Jinhui Ding,Richard A Hickman,Thor D Stein,Yevgeniya Abramzon,Sarah Ahmed,Marya S Sabir,Makayla K Portley,Arianna Tucci,Kristina Ibáñez,F N U Shankaracharya,Pamela Keagle,Giacomina Rossi,Paola Caroppo,Fabrizio Tagliavini,Maria L Waldo,Per M Johansson,Christer F Nilsson,American Genome Center (TAGC),FALS Sequencing Consortium,Genomics England Research Consortium,International ALS/FTD Genomics Consortium (iAFGC),International FTD Genetics Consortium (IFGC),International LBD Genomics Consortium (iLBDGC),NYGC ALS Consortium,PROSPECT Consortium,James B Rowe,Luisa Benussi,Giuliano Binetti,Roberta Ghidoni,Edwin Jabbari,Coralie Viollet,Jonathan D Glass,Andrew B Singleton,Vincenzo Silani,Owen A Ross,Mina Ryten,Ali Torkamani,Toshiko Tanaka,Luigi Ferrucci,Susan M Resnick,Stuart Pickering-Brown,Christopher B Brady,Neil Kowal,John A Hardy,Vivianna Van Deerlin,Jean Paul Vonsattel,Matthew B Harms,Huw R Morris,Raffaele Ferrari,John E Landers,Adriano Chiò,J Raphael Gibbs,Clifton L Dalgard,Sonja W Scholz,Bryan J Traynor
Source: Neuron
We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We...
-
Friday, October 16, 2020
Author(s): Sabrina Paganoni,Suzanne Hendrix,Samuel P Dickson,Newman Knowlton,Eric A Macklin,James D Berry,Michael A Elliott,Samuel Maiser,Chafic Karam,James B Caress,Margaret Ayo Owegi,Adam Quick,James Wymer,Stephen A Goutman,Daragh Heitzman,Terry D Heiman-Patterson,Carlayne E Jackson,Colin Quinn,Jeffrey D Rothstein,Edward J Kasarskis,Jonathan Katz,Liberty Jenkins,Shafeeq Ladha,Timothy M Miller,Stephen N Scelsa,Tuan H Vu,Christina N Fournier,Jonathan D Glass,Kristin M Johnson,Andrea Swenson,Namita A Goyal,Gary L Pattee,Patricia L Andres,Suma Babu,Marianne Chase,Derek Dagostino,Meghan Hall,Gale Kittle,Matthew Eydinov,Michelle McGovern,Joseph Ostrow,Lindsay Pothier,Rebecca Randall,Jeremy M Shefner,Alexander V Sherman,Maria E St Pierre,Eric Tustison,Prasha Vigneswaran,Jason Walker,Hong Yu,James Chan,Janet Wittes,Zi-Fan Yu,Joshua Cohen,Justin Klee,Kent Leslie,Rudolph E Tanzi,Walter Gilbert,Patrick D Yeramian,David Schoenfeld,Merit E Cudkowicz
Source: Muscle & nerve
An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An...
-
Monday, September 21, 2020
Author(s): Gijs H P Tazelaar,Steven Boeynaems,Mathias De Decker,Joke J F A van Vugt,Lindy Kool,H Stephan Goedee,Russell L McLaughlin,William Sproviero,Alfredo Iacoangeli,Matthieu Moisse,Maarten Jacquemyn,Dirk Daelemans,Annelot M Dekker,Rick A van der Spek,Henk-Jan Westeneng,Kevin P Kenna,Abdelilah Assialioui,Nica Da Silva,Project MinE ALS Sequencing Consortium,Mónica Povedano,Jesus S Mora Pardina,Orla Hardiman,François Salachas,Stéphanie Millecamps,Patrick Vourc'h,Philippe Corcia,Philippe Couratier,Karen E Morrison,Pamela J Shaw,Christopher E Shaw,R Jeroen Pasterkamp,John E Landers,Ludo Van Den Bosch,Wim Robberecht,Ammar Al-Chalabi,Leonard H van den Berg,Philip Van Damme,Jan H Veldink,Michael A van Es
Source: Brain communications
Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by...
-
Thursday, September 03, 2020
Author(s): Sabrina Paganoni,Eric A Macklin,Suzanne Hendrix,James D Berry,Michael A Elliott,Samuel Maiser,Chafic Karam,James B Caress,Margaret A Owegi,Adam Quick,James Wymer,Stephen A Goutman,Daragh Heitzman,Terry Heiman-Patterson,Carlayne E Jackson,Colin Quinn,Jeffrey D Rothstein,Edward J Kasarskis,Jonathan Katz,Liberty Jenkins,Shafeeq Ladha,Timothy M Miller,Stephen N Scelsa,Tuan H Vu,Christina N Fournier,Jonathan D Glass,Kristin M Johnson,Andrea Swenson,Namita A Goyal,Gary L Pattee,Patricia L Andres,Suma Babu,Marianne Chase,Derek Dagostino,Samuel P Dickson,Noel Ellison,Meghan Hall,Kent Hendrix,Gale Kittle,Michelle McGovern,Joseph Ostrow,Lindsay Pothier,Rebecca Randall,Jeremy M Shefner,Alexander V Sherman,Eric Tustison,Prasha Vigneswaran,Jason Walker,Hong Yu,James Chan,Janet Wittes,Joshua Cohen,Justin Klee,Kent Leslie,Rudolph E Tanzi,Walter Gilbert,Patrick D Yeramian,David Schoenfeld,Merit E Cudkowicz
Source: The New England journal of medicine
CONCLUSIONS: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).
-
Thursday, July 09, 2020
Author(s): Christian Mueller,James D Berry,Diane M McKenna-Yasek,Gwladys Gernoux,Margaret A Owegi,Lindsay M Pothier,Catherine L Douthwright,Dario Gelevski,Sarah D Luppino,Meghan Blackwood,Nicholas S Wightman,Derek H Oakley,Matthew P Frosch,Terrence R Flotte,Merit E Cudkowicz,Robert H Brown
Source: The New England journal of medicine
Two patients with familial amyotrophic lateral sclerosis (ALS) and mutations in the gene encoding superoxide dismutase 1 (SOD1) were treated with a single intrathecal infusion of adeno-associated virus encoding a microRNA targeting SOD1. In Patient 1, SOD1 levels in spinal cord tissue as analyzed on autopsy were lower than corresponding levels in untreated patients with SOD1-mediated ALS and in healthy controls. Levels of SOD1 in cerebrospinal fluid were transiently and only slightly lower in...
-
Tuesday, July 07, 2020
Author(s): Giulia Murtas,Silvia Sacchi,Meenakshi Sundaram Kumar,Daryl A Bosco,Loredano Pollegioni
Source: Free radical research
pLG72 is a primate-specific protein of enigmatic function that was proposed to modulate mitochondria fragmentation and the activity of the peroxisomal enzyme D-amino acid oxidase (DAAO). DAAO is deputed to degradation of the NMDA receptor co-agonist D-serine in human brain and the R199W substitution in DAAO was identified in a familial case of amyotrophic lateral sclerosis (ALS). A recent work reported that U87 glioblastoma cells ectopically expressing pLG72 showed a lower proliferation,...
-
Wednesday, June 10, 2020
Author(s): Fen Huang,Yuda Zhu,Jennifer Hsiao-Nakamoto,Xinyan Tang,Jason C Dugas,Miriam Moscovitch-Lopatin,Jonathan D Glass,Robert H Brown,Shafeeq S Ladha,David Lacomis,Jeffrey M Harris,Kimberly Scearce-Levie,Carole Ho,Robert Bowser,James D Berry
Source: Annals of clinical and translational neurology
OBJECTIVE: To investigate neurodegenerative and inflammatory biomarkers in people with amyotrophic lateral sclerosis (PALS), evaluate their predictive value for ALS progression rates, and assess their utility as pharmacodynamic biomarkers for monitoring treatment effects.
-
Saturday, May 16, 2020
Author(s): Dick Schijven,Remi Stevelink,Mark McCormack,Wouter van Rheenen,Jurjen J Luykx,Bobby P C Koeleman,Jan H Veldink,Project MinE ALS GWAS Consortium,International League Against Epilepsy Consortium on Complex Epilepsies
Source: Neurobiology of aging
Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants...
-
Thursday, April 09, 2020
Author(s): Gopinath Krishnan,Yu Zhang,Yuanzheng Gu,Mark W Kankel,Fen-Biao Gao,Sandra Almeida
Source: Acta neuropathologica
No abstract
-
Friday, January 24, 2020
Author(s): Allison M Keeler,Marina Zieger,Carson Semple,Logan Pucci,Alessandra Veinbachs,Robert H Brown,Christian Mueller,Mai K ElMallah
Source: Molecular therapy. Methods & clinical development
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in death from respiratory failure. No cure exists for this devastating disease, but therapy that directly targets the respiratory system has the potential to prolong survival and improve quality of life in some cases of ALS. The objective of this study was to enhance breathing and prolong survival by suppressing superoxide dismutase 1 (SOD1) expression in respiratory motor neurons using adeno-associated virus...
-
Friday, December 20, 2019
Author(s): Irit Reichenstein,Chen Eitan,Sandra Diaz-Garcia,Guy Haim,Iddo Magen,Aviad Siany,Mariah L Hoye,Natali Rivkin,Tsviya Olender,Beata Toth,Revital Ravid,Amitai D Mandelbaum,Eran Yanowski,Jing Liang,Jeffrey K Rymer,Rivka Levy,Gilad Beck,Elena Ainbinder,Sali M K Farhan,Kimberly A Lennox,Nicole M Bode,Mark A Behlke,Thomas Möller,Smita Saxena,Cristiane A M Moreno,Giancarlo Costaguta,Kristel R van Eijk,Hemali Phatnani,Ammar Al-Chalabi,A Nazli Başak,Leonard H van den Berg,Orla Hardiman,John E Landers,Jesus S Mora,Karen E Morrison,Pamela J Shaw,Jan H Veldink,Samuel L Pfaff,Ofer Yizhar,Christina Gross,Robert H Brown,John M Ravits,Matthew B Harms,Timothy M Miller,Eran Hornstein
Source: Science translational medicine
Motor neuron-specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1...
-
Sunday, December 01, 2019
Author(s): Yeliz Yuva-Aydemir,Sandra Almeida,Gopinath Krishnan,Tania F Gendron,Fen-Biao Gao
Source: Nature communications
Expanded GGGGCC (G(4)C(2)) repeats in C9ORF72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How RNAs containing expanded G(4)C(2) repeats are transcribed in human neurons is largely unknown. Here we describe a Drosophila model in which poly(GR) expression in adult neurons causes axonal and locomotor defects and premature death without apparent TDP-43 pathology. In an unbiased genetic screen, partial loss of Lilliputian (Lilli) activity strongly suppresses poly(GR)...
-
Wednesday, November 20, 2019
Author(s): James D Berry,Merit E Cudkowicz,Anthony J Windebank,Nathan P Staff,Margaret Owegi,Katherine Nicholson,Diane McKenna-Yasek,Yossef S Levy,Natalie Abramov,Haggai Kaspi,Munish Mehra,Revital Aricha,Yael Gothelf,Robert H Brown
Source: Neurology
CONCLUSION: A single-dose transplantation of MSC-NTF cells is safe and demonstrated early promising signs of efficacy. This establishes a clear path forward for a multidose randomized clinical trial of intrathecal autologous MSC-NTF cell transplantation in ALS.
-
Friday, October 18, 2019
Author(s): Mathieu Bartoletti,Daryl A Bosco,Sandrine Da Cruz,Clotilde Lagier-Tourenne,Nicole Liachko,Sebastian Markmiller,Kristin M Webster,Kristi A Wharton
Source: The Journal of neuroscience : the official journal of the Society for Neuroscience
A fundamental question regarding the etiology of amyotrophic lateral sclerosis (ALS) is whether the various gene mutations associated with the disease converge on a single molecular pathway or act through multiple pathways to trigger neurodegeneration. Notably, several of the genes and cellular processes implicated in ALS have also been linked to frontotemporal dementia (FTD), suggesting these two diseases share common origins with varied clinical presentations. Scientists are rapidly...
-
Friday, October 04, 2019
Author(s): Alexander J Cammack,Nazem Atassi,Theodore Hyman,Leonard H van den Berg,Matthew Harms,Robert H Baloh,Robert H Brown,Michael A van Es,Jan H Veldink,Balint S de Vries,Jeffrey D Rothstein,Caroline Drain,Jennifer Jockel-Balsarotti,Amber Malcolm,Sonia Boodram,Amber Salter,Nicholas Wightman,Hong Yu,Alexander V Sherman,Thomas J Esparza,Diane McKenna-Yasek,Margaret A Owegi,Catherine Douthwright,Alzheimer's Disease Neuroimaging Initiative,Alexander McCampbell,Toby Ferguson,Carlos Cruchaga,Merit Cudkowicz,Timothy M Miller
Source: Neurology
CONCLUSIONS: We present a thorough investigation of C9ALS natural history, providing the basis for C9ALS clinical trial design. We found that clinical features of this genetic subset are less variant than in singleton ALS. In addition, we identified important correlations of C9ALS patient pathologies with clinical and demographic data.
-
Sunday, August 25, 2019
Author(s): Anthony Giampetruzzi,Eric W Danielson,Valentina Gumina,Maryangel Jeon,Sivakumar Boopathy,Robert H Brown,Antonia Ratti,John E Landers,Claudia Fallini
Source: Nature communications
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology. Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS and other neurodegenerative diseases, the molecular mechanisms modulating the nuclear pore function are still largely unknown. Here we show that genetic and pharmacological modulation of actin polymerization disrupts nuclear pore integrity, nuclear import, and downstream pathways such as mRNA...
-
Tuesday, July 09, 2019
Author(s): Rick A A van der Spek,Wouter van Rheenen,Sara L Pulit,Kevin P Kenna,Leonard H van den Berg,Jan H Veldink,Project MinE ALS Sequencing Consortium
Source: Amyotrophic lateral sclerosis & frontotemporal degeneration
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative disease affecting one in 350 people. The aim of Project MinE is to elucidate the pathophysiology of ALS through whole-genome sequencing at least 15,000 ALS patients and 7500 controls at 30× coverage. Here, we present the Project MinE data browser ( databrowser.projectmine.com ), a unique and intuitive one-stop, open-access server that provides detailed information on genetic variation analyzed in a new and still...
-
Friday, May 17, 2019
Author(s): Maeve Tischbein,Desiree M Baron,Yen-Chen Lin,Katherine V Gall,John E Landers,Claudia Fallini,Daryl A Bosco
Source: The Journal of biological chemistry
Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for neurodegenerative disease-linked RNA-binding proteins (RBPs) in the cellular stress response. However, the relationships between excitotoxicity, RBP function, and disease have not been explored. Here, using primary cortical and motor neurons, we found that excitotoxicity induced the translocation...
-
Thursday, May 16, 2019
Author(s): So Yoen Choi,Rodrigo Lopez-Gonzalez,Gopinath Krishnan,Hannah L Phillips,Alissa Nana Li,William W Seeley,Wei-Dong Yao,Sandra Almeida,Fen-Biao Gao
Source: Nature neuroscience
The GGGGCC repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, it is not known which dysregulated molecular pathways are primarily responsible for disease initiation or progression. We established an inducible mouse model of poly(GR) toxicity in which (GR)(80) gradually accumulates in cortical excitatory neurons. Low-level poly(GR) expression induced FTD/ALS-associated synaptic dysfunction and behavioral...
-
Tuesday, April 16, 2019
Author(s): Hyerim Kim,Junghwa Lim,Han Bao,Bin Jiao,Se Min Canon,Michael P Epstein,Keqin Xu,Jie Jiang,Janani Parameswaran,Yingjie Li,Kenneth H Moberg,John E Landers,Christina Fournier,Emily G Allen,Jonathan D Glass,Thomas S Wingo,Peng Jin
Source: Human molecular genetics
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive muscular atrophy and respiratory failure. The G4C2 repeat expansion in the C9orf72 gene is the most prevalent genetic risk for ALS. Mutation carriers (C9ALS) display variability in phenotypes such as age-at-onset and duration, suggesting the existence of additional genetic factors. Here we introduce a three-step gene discovery strategy to identify genetic factors modifying the risk of both C9ALS and...
-
Thursday, April 04, 2019
Author(s): Sahar Gelfman,Sarah Dugger,Cristiane de Araujo Martins Moreno,Zhong Ren,Charles J Wolock,Neil A Shneider,Hemali Phatnani,Elizabeth T Cirulli,Brittany N Lasseigne,Tim Harris,Tom Maniatis,Guy A Rouleau,Robert H Brown,Aaron D Gitler,Richard M Myers,Slavé Petrovski,Andrew Allen,David B Goldstein,Matthew B Harms
Source: Genome research
Large-scale sequencing efforts in amyotrophic lateral sclerosis (ALS) have implicated novel genes using gene-based collapsing methods. However, pathogenic mutations may be concentrated in specific genic regions. To address this, we developed two collapsing strategies: One focuses rare variation collapsing on hom*ology-based protein domains as the unit for collapsing, and the other is a gene-level approach that, unlike standard methods, leverages existing evidence of purifying selection against...
-
Thursday, February 28, 2019
Author(s): Johnathan Cooper-Knock,Tobias Moll,Tennore Ramesh,Lydia Castelli,Alexander Beer,Henry Robins,Ian Fox,Isabell Niedermoser,Philip Van Damme,Matthieu Moisse,Wim Robberecht,Orla Hardiman,Monica P Panades,Abdelilah Assialioui,Jesus S Mora,A Nazli Basak,Karen E Morrison,Christopher E Shaw,Ammar Al-Chalabi,John E Landers,Matthew Wyles,Paul R Heath,Adrian Higginbottom,Theresa Walsh,Mbombe Kazoka,Christopher J McDermott,Guillaume M Hautbergue,Janine Kirby,Pamela J Shaw
Source: Cell reports
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport, and protein homeostasis. We report ALS-causing mutations within the gene encoding the glycosyltransferase GLT8D1. Exome sequencing in an autosomal-dominant ALS pedigree identified p.R92C mutations in GLT8D1, which co-segregate with disease. Sequencing of local and international cohorts...
-
Wednesday, February 27, 2019
Author(s): Desiree M Baron,Tyler Matheny,Yen-Chen Lin,John D Leszyk,Kevin Kenna,Katherine V Gall,David P Santos,Maeve Tischbein,Salome Funes,Lawrence J Hayward,Evangelos Kiskinis,John E Landers,Roy Parker,Scott A Shaffer,Daryl A Bosco
Source: Human molecular genetics
Aberrant translational repression is a feature of multiple neurodegenerative diseases. The association between disease-linked proteins and stress granules further implicates impaired stress responses in neurodegeneration. However, our knowledge of the proteins that evade translational repression is incomplete. It is also unclear whether disease-linked proteins influence the proteome under conditions of translational repression. To address these questions, a quantitative proteomics approach was...
-
Friday, November 02, 2018
Author(s): Florie Borel,Gwladys Gernoux,Huaming Sun,Rachel Stock,Meghan Blackwood,Robert H Brown,Christian Mueller
Source: Science translational medicine
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease caused by degeneration of motor neurons leading to rapidly progressive paralysis. About 10% of cases are caused by gain-of-function mutations that are transmitted as dominant traits. A potential therapy for these cases is to suppress the expression of the mutant gene. Here, we investigated silencing of SOD1, a gene commonly mutated in familial ALS, using an adeno-associated virus (AAV) encoding an artificial microRNA (miRNA)...
-
Monday, October 22, 2018
Author(s): Gijs H P Tazelaar,Annelot M Dekker,Joke J F A van Vugt,Rick A van der Spek,Henk-Jan Westeneng,Lindy J B G Kool,Kevin P Kenna,Wouter van Rheenen,Sara L Pulit,Russell L McLaughlin,William Sproviero,Alfredo Iacoangeli,Annemarie Hübers,David Brenner,Karen E Morrison,Pamela J Shaw,Christopher E Shaw,Monica Povedano Panadés,Jesus S Mora Pardina,Jonathan D Glass,Orla Hardiman,Ammar Al-Chalabi,Philip van Damme,Wim Robberecht,John E Landers,Albert C Ludolph,Jochen H Weishaupt,Leonard H van den Berg,Jan H Veldink,Michael A van Es,Project MinE ALS Sequencing Consortium
Source: Neurobiology of aging
NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to...
-
Wednesday, July 25, 2018
Author(s): Danilo B Medinas,Pablo Rozas,Francisca Martínez Traub,Ute Woehlbier,Robert H Brown,Daryl A Bosco,Claudio Hetz
Source: Proceedings of the National Academy of Sciences of the United States of America
Abnormal modifications to mutant superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (fALS). Misfolding of wild-type SOD1 (SOD1^(WT)) is also observed in postmortem tissue of a subset of sporadic ALS (sALS) cases, but cellular and molecular mechanisms generating abnormal SOD1^(WT) species are unknown. We analyzed aberrant human SOD1^(WT) species over the lifetime of transgenic mice and found the accumulation of disulfide-cross-linked high-molecular-weight SOD1^(WT)...
-
Tuesday, July 24, 2018
Author(s): Martina de Majo,Simon D Topp,Bradley N Smith,Agnes L Nishimura,Han-Jou Chen,Athina Soragia Gkazi,Jack Miller,Chun Hao Wong,Caroline Vance,Frank Baas,Anneloor L M A Ten Asbroek,Kevin P Kenna,Nicola Ticozzi,Alberto Garcia Redondo,Jesús Esteban-Pérez,Cinzia Tiloca,Federico Verde,Stefano Duga,Karen E Morrison,Pamela J Shaw,Janine Kirby,Martin R Turner,Kevin Talbot,Orla Hardiman,Jonathan D Glass,Jacqueline de Belleroche,Cinzia Gellera,Antonia Ratti,Ammar Al-Chalabi,Robert H Brown,Vincenzo Silani,John E Landers,Christopher E Shaw
Source: Neurobiology of aging
Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency; however, many other mutations are missense with unknown functional effects. We exome sequenced 699 familial amyotrophic lateral sclerosis patients and identified 16 TBK1 novel or extremely rare protein-changing variants. We characterized a subset of these: p.G217R, p.R357X, and p.C471Y. Here, we show that the...
-
Wednesday, July 18, 2018
Author(s): Project MinE ALS Sequencing Consortium
Source: Annals of neurology
OBJECTIVE: After the initial report of a CHCHD10 mutation in mitochondrial disease with features resembling amyotrophic lateral sclerosis (ALS), CHCHD10 mutations have been considered to be a frequent cause for ALS. However, the exact pathogenicity and clinical significance of these mutations remain unclear. Here, we aimed to determine the role of CHCHD10 mutations in ALS.
-
Saturday, June 30, 2018
Author(s): Project MinE ALS Sequencing Consortium
Source: European journal of human genetics : EJHG
The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility to disease. We have therefore begun Project MinE, an international collaboration that seeks to analyze whole-genome sequence data of at least 15 000 ALS patients and 7500 controls. Here, we report on the design of Project MinE and pilot analyses of successfully sequenced 1169 ALS patients and 608 controls drawn...
-
Thursday, June 07, 2018
Author(s): Matthew A White,Eosu Kim,Amanda Duffy,Robert Adalbert,Benjamin U Phillips,Owen M Peters,Jodie Stephenson,Sujeong Yang,Francesca Massenzio,Ziqiang Lin,Simon Andrews,Anne Segonds-Pichon,Jake Metterville,Lisa M Saksida,Richard Mead,Richard R Ribchester,Youssef Barhomi,Thomas Serre,Michael P Coleman,Justin R Fallon,Timothy J Bussey,Robert H Brown,Jemeen Sreedharan
Source: Nature neuroscience
In the version of this article initially published, the footnote number 17 was missing from the author list for the two authors who contributed equally. Also, the authors have added a middle initial for author Justin R. Fallon and an acknowledgement to the Babraham Institute Imaging Facility and Sequencing Core Facility. The errors have been corrected in the HTML and PDF versions of the article.
-
Monday, May 07, 2018
Author(s): Yeliz Yuva-Aydemir,Sandra Almeida,Fen-Biao Gao
Source: Trends in neurosciences
GGGGCC (G(4)C(2)) repeat expansion in C9ORF72 is the most common genetic cause of ALS and FTD. An important issue is how repeat RNAs and their translation products, various dipeptide repeat (DPR) proteins, cause neurodegeneration. Drosophila has been widely used to model G(4)C(2) repeat RNA and DPR protein toxicity. Overexpression of disease molecules in flies has revealed important molecular insights. These have been validated and further explored in human neurons differentiated from induced...
-
Thursday, April 12, 2018
Author(s): Ammar Al-Chalabi,Robert H Brown
Source: The New England journal of medicine
No abstract
-
Saturday, March 24, 2018
Author(s): Aude Nicolas,Kevin P Kenna,Alan E Renton,Nicola Ticozzi,Faraz fa*ghri,Ruth Chia,Janice A Dominov,Brendan J Kenna,Mike A Nalls,Pamela Keagle,Alberto M Rivera,Wouter van Rheenen,Natalie A Murphy,Joke J F A van Vugt,Joshua T Geiger,Rick A Van der Spek,Hannah A Pliner,None Shankaracharya,Bradley N Smith,Giuseppe Marangi,Simon D Topp,Yevgeniya Abramzon,Athina Soragia Gkazi,John D Eicher,Aoife Kenna,ITALSGEN Consortium,Gabriele Mora,Andrea Calvo,Letizia Mazzini,Nilo Riva,Jessica Mandrioli,Claudia Caponnetto,Stefania Battistini,Paolo Volanti,Vincenzo La Bella,Francesca L Conforti,Giuseppe Borghero,Sonia Messina,Isabella L Simone,Francesca Trojsi,Fabrizio Salvi,Francesco O Logullo,Sandra D'Alfonso,Lucia Corrado,Margherita Capasso,Luigi Ferrucci,Genomic Translation for ALS Care (GTAC) Consortium,Cristiane de Araujo Martins Moreno,Sitharthan Kamalakaran,David B Goldstein,ALS Sequencing Consortium,Aaron D Gitler,Tim Harris,Richard M Myers,NYGC ALS Consortium,Hemali Phatnani,Rajeeva Lochan Musunuri,Uday Shankar Evani,Avinash Abhyankar,Michael C Zody,Answer ALS Foundation,Julia Kaye,Steven Finkbeiner,Stacia K Wyman,Alex LeNail,Leandro Lima,Ernest Fraenkel,Clive N Svendsen,Leslie M Thompson,Jennifer E Van Eyk,James D Berry,Timothy M Miller,Stephen J Kolb,Merit Cudkowicz,Emily Baxi,Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium,Michael Benatar,J Paul Taylor,Evadnie Rampersaud,Gang Wu,Joanne Wuu,SLAGEN Consortium,Giuseppe Lauria,Federico Verde,Isabella Fogh,Cinzia Tiloca,Giacomo P Comi,Gianni Sorarù,Cristina Cereda,French ALS Consortium,Philippe Corcia,Hannu Laaksovirta,Liisa Myllykangas,Lilja Jansson,Miko Valori,John Ealing,Hisham Hamdalla,Sara Rollinson,Stuart Pickering-Brown,Richard W Orrell,Katie C Sidle,Andrea Malaspina,John Hardy,Andrew B Singleton,Janel O Johnson,Sampath Arepalli,Peter C Sapp,Diane McKenna-Yasek,Meraida Polak,Seneshaw Asress,Safa Al-Sarraj,Andrew King,Claire Troakes,Caroline Vance,Jacqueline de Belleroche,Frank Baas,Anneloor L M A Ten Asbroek,José Luis Muñoz-Blanco,Dena G Hernandez,Jinhui Ding,J Raphael Gibbs,Sonja W Scholz,Mary Kay Floeter,Roy H Campbell,Francesco Landi,Robert Bowser,Stefan M Pulst,John M Ravits,Daniel J L MacGowan,Janine Kirby,Erik P Pioro,Roger Pamphlett,James Broach,Glenn Gerhard,Travis L Dunckley,Christopher B Brady,Neil W Kowall,Juan C Troncoso,Isabelle Le Ber,Kevin Mouzat,Serge Lumbroso,Terry D Heiman-Patterson,Freya Kamel,Ludo Van Den Bosch,Robert H Baloh,Tim M Strom,Thomas Meitinger,Aleksey Shatunov,Kristel R Van Eijk,Mamede de Carvalho,Maarten Kooyman,Bas Middelkoop,Matthieu Moisse,Russell L McLaughlin,Michael A Van Es,Markus Weber,Kevin B Boylan,Marka Van Blitterswijk,Rosa Rademakers,Karen E Morrison,A Nazli Basak,Jesús S Mora,Vivian E Drory,Pamela J Shaw,Martin R Turner,Kevin Talbot,Orla Hardiman,Kelly L Williams,Jennifer A Fifita,Garth A Nicholson,Ian P Blair,Guy A Rouleau,Jesús Esteban-Pérez,Alberto García-Redondo,Ammar Al-Chalabi,Project MinE ALS Sequencing Consortium,Ekaterina Rogaeva,Lorne Zinman,Lyle W Ostrow,Nicholas J Maragakis,Jeffrey D Rothstein,Zachary Simmons,Johnathan Cooper-Knock,Alexis Brice,Stephen A Goutman,Eva L Feldman,Summer B Gibson,Franco Taroni,Antonia Ratti,Cinzia Gellera,Philip Van Damme,Wim Robberecht,Pietro Fratta,Mario Sabatelli,Christian Lunetta,Albert C Ludolph,Peter M Andersen,Jochen H Weishaupt,William Camu,John Q Trojanowski,Vivianna M Van Deerlin,Robert H Brown,Leonard H van den Berg,Jan H Veldink,Matthew B Harms,Jonathan D Glass,David J Stone,Pentti Tienari,Vincenzo Silani,Adriano Chiò,Christopher E Shaw,Bryan J Traynor,John E Landers
Source: Neuron
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are...
-
Wednesday, March 21, 2018
Author(s): Matthew A White,Eosu Kim,Amanda Duffy,Robert Adalbert,Benjamin U Phillips,Owen M Peters,Jodie Stephenson,Sujeong Yang,Francesca Massenzio,Ziqiang Lin,Simon Andrews,Anne Segonds-Pichon,Jake Metterville,Lisa M Saksida,Richard Mead,Richard R Ribchester,Youssef Barhomi,Thomas Serre,Michael P Coleman,Justin R Fallon,Timothy J Bussey,Robert H Brown,Jemeen Sreedharan
Source: Nature neuroscience
Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterized by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here we have created a TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43^(Q331K) mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically,...
-
Thursday, December 14, 2017
Author(s): Rick A van der Spek,Wouter van Rheenen,Sara L Pulit,Kevin P Kenna,Nicola Ticozzi,Maarten Kooyman,Russell L Mclaughlin,Matthieu Moisse,Kristel R van Eijk,Joke J F A van Vugt,Alfredo Iacoangeli,Peter Andersen,A Nazli Basak,Ian Blair,Mamede de Carvalho,Adriano Chio,Philippe Corcia,Phillipe Couratier,Vivian E Drory,Jonathan D Glass,Orla Hardiman,Jesús S Mora,Karen E Morrison,Miguel Mitne-Neto,Wim Robberecht,Pamela J Shaw,Monica P Panadés,Philip van Damme,Vincenzo Silani,Marc Gotkine,Markus Weber,Michael A van Es,John E Landers,Ammar Al-Chalabi,Leonard H van den Berg,Jan H Veldink,PROJECT MINE ALS SEQUENCING CONSORTIUM
Source: Amyotrophic lateral sclerosis & frontotemporal degeneration
No abstract
-
Saturday, November 25, 2017
Author(s): Johnathan Cooper-Knock,Henry Robins,Isabell Niedermoser,Matthew Wyles,Paul R Heath,Adrian Higginbottom,Theresa Walsh,Mbombe Kazoka,Project MinE ALS Sequencing Consortium,Paul G Ince,Guillaume M Hautbergue,Christopher J McDermott,Janine Kirby,Pamela J Shaw
Source: Frontiers in molecular neuroscience
Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this...
-
Sunday, September 17, 2017
Author(s): Fen-Biao Gao,Sandra Almeida,Rodrigo Lopez-Gonzalez
Source: The EMBO journal
Frontotemporal dementia (FTD), the second most common form of dementia in people under 65 years of age, is characterized by progressive atrophy of the frontal and/or temporal lobes. FTD overlaps extensively with the motor neuron disease amyotrophic lateral sclerosis (ALS), especially at the genetic level. Both FTD and ALS can be caused by many mutations in the same set of genes; the most prevalent of these mutations is a GGGGCC repeat expansion in the first intron of C9ORF72 As shown by recent...
