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ALS Publications by UMass Chan Research Specialists

Total: 50 results

  • Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data

    Tuesday, October 22, 2024
    Author(s): Sara Saez-Atienzar,Cleide Dos Santos Souza,Ruth Chia,Selina N Beal,Ileana Lorenzini,Ruili Huang,Jennifer Levy,Camelia Burciu,Jinhui Ding,J Raphael Gibbs,Ashley Jones,Ramita Dewan,Viviana Pensato,Silvia Peverelli,Lucia Corrado,Joke J F A van Vugt,Wouter van Rheenen,Ceren Tunca,Elif Bayraktar,Menghang Xia,International ALS Genomics Consortium,ITALSGEN Consortium,SLAGEN Consortium,Project MinE ALS Sequencing Consortium,Alfredo Iacoangeli,Aleksey Shatunov,Cinzia Tiloca,Nicola Ticozzi,Federico Verde,Letizia Mazzini,Kevin Kenna,Ahmad Al Khleifat,Sarah Opie-Martin,Flavia Raggi,Massimiliano Filosto,Stefano Cotti Piccinelli,Alessandro Padovani,Stella Gagliardi,Maurizio Inghilleri,Alessandra Ferlini,Rosario Vasta,Andrea Calvo,Cristina Moglia,Antonio Canosa,Umberto Manera,Maurizio Grassano,Jessica Mandrioli,Gabriele Mora,Christian Lunetta,Raffaella Tanel,Francesca Trojsi,Patrizio Cardinali,Salvatore Gallone,Maura Brunetti,Daniela Galimberti,Maria Serpente,Chiara Fenoglio,Elio Scarpini,Giacomo P Comi,Stefania Corti,Roberto Del Bo,Mauro Ceroni,Giuseppe Lauria Pinter,Franco Taroni,Eleonora Dalla Bella,Enrica Bersano,Charles J Curtis,Sang Hyuck Lee,Raymond Chung,Hamel Patel,Karen E Morrison,Johnathan Cooper-Knock,Pamela J Shaw,Gerome Breen,Richard J B Dobson,Clifton L Dalgard,American Genome Center,Sonja W Scholz,Ammar Al-Chalabi,Leonard H van den Berg,Russell McLaughlin,Orla Hardiman,Cristina Cereda,Gianni Sorarù,Sandra D'Alfonso,Siddharthan Chandran,Suvankar Pal,Antonia Ratti,Cinzia Gellera,Kory Johnson,Tara Doucet-O'Hare,Nicholas Pasternack,Tongguang Wang,Avindra Nath,Gabriele Siciliano,Vincenzo Silani,Ayşe Nazlı Başak,Jan H Veldink,William Camu,Jonathan D Glass,John E Landers,Adriano Chiò,Rita Sattler,Christopher E Shaw,Laura Ferraiuolo,Isabella Fogh,Bryan J Traynor
    Source: Cell genomics
    Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these...

  • Association Between LACE+ Index Risk Category and 90-Day Mortality After Stroke

    Monday, October 14, 2024
    Author(s): Adalia Jun-O'Connell,Brian Silver,Eliza Grigoriciuc,Akanksha Gulati,Kimiyoshi J Kobayashi,Nils Henninger
    Source: Neurology. Clinical practice
    BACKGROUND AND OBJECTIVES: A higher LACE+ index risk category (defined as LACE+ score ≥78) typically calculated before hospital discharge has been associated with increased risk of unplanned 30-day hospital readmissions and early death after hospital discharge. However, its utility to predict poststroke mortality is unknown. Here, we examined whether the LACE+ index risk category assessed at both discharge (dLACE+) and admission (aLACE+) was associated with 90-day mortality after stroke.

  • Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs

    Thursday, September 05, 2024
    Author(s): James W Gilbert,Zachary Kennedy,Bruno M D C Godinho,Ashley Summers,Alexandra Weiss,Dimas Echeverria,Brianna Bramato,Nicholas McHugh,David Cooper,Ken Yamada,Matthew Hassler,Hélène Tran,Fen Biao Gao,Robert H Brown,Anastasia Khvorova
    Source: Molecular therapy. Nucleic acids
    A hexanucleotide (G(4)C(2)) repeat expansion (HRE) within intron one of C9ORF72 is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). C9ORF72 haploinsufficiency, formation of RNA foci, and production of dipeptide repeat (DPR) proteins have been proposed as mechanisms of disease. Here, we report the first example of disease-modifying siRNAs for C9ORF72 driven ALS/FTD. Using a combination of reporter assay and primary cortical neurons derived from a...

  • RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice

    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...

  • Author Correction: The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration

    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

  • The exocyst subunit EXOC2 regulates the toxicity of expanded GGGGCC repeats in C9ORF72-ALS/FTD

    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...

  • Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease

    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...

  • Computing linkage disequilibrium aware genome embeddings using autoencoders

    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...

  • Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS

    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.

  • Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial

    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.

  • Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes

    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.

  • Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia

    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...

  • Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS

    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...

  • Loss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosis

    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...

  • Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo

    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...

  • Mature iPSC-derived astrocytes of an ALS/FTD patient carrying the TDP43(A90V) mutation display a mild reactive state and release polyP toxic to motoneurons

    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...

  • Amyotrophic lateral sclerosis

    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...

  • Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import

    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...

  • Repeated mild traumatic brain injury triggers pathology in asymptomatic C9ORF72 transgenic mice

    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...

  • Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia

    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...

  • Stroke nurse navigator utilization reduces unplanned 30-day readmission in stroke patients treated with thrombolysis

    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.

  • Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias

    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...

  • Moderate intrinsic phenotypic alterations in C9orf72 ALS/FTD iPSC-microglia despite the presence of C9orf72 pathological features

    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...

  • Design and Statistical Innovations in a Platform Trial for Amyotrophic Lateral Sclerosis

    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...

  • Genetic variability in sporadic amyotrophic lateral sclerosis

    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...

  • Amyotrophic lateral sclerosis: translating genetic discoveries into therapies

    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...

  • Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival

    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...

  • Clinical testing panels for ALS: global distribution, consistency, and challenges

    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...

  • Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population

    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...

  • Interactions between FUS and the C-terminal Domain of Nup62 are Sufficient for their Co-phase Separation into Amorphous Assemblies

    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...

  • How villains are made: The translation of dipeptide repeat proteins in C9ORF72-ALS/FTD

    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...

  • Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data

    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...

  • Anti-SOD1 Nanobodies That Stabilize Misfolded SOD1 Proteins Also Promote Neurite Outgrowth in Mutant SOD1 Human Neurons

    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...

  • A reference human induced pluripotent stem cell line for large-scale collaborative studies

    Friday, December 02, 2022
    Author(s): Caroline B Pantazis,Andrian Yang,Erika Lara,Justin A McDonough,Cornelis Blauwendraat,Lirong Peng,Hideyuki Oguro,Jitendra Kanaujiya,Jizhong Zou,David Sebesta,Gretchen Pratt,Erin Cross,Jeffrey Blockwick,Philip Buxton,Lauren Kinner-Bibeau,Constance Medura,Christopher Tompkins,Stephen Hughes,Marianita Santiana,Faraz Faghri,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...

  • The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration

    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...

  • CRISPR/Cas9-mediated excision of ALS/FTD-causing hexanucleotide repeat expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro

    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...

  • The impact of age on genetic testing decisions in amyotrophic lateral sclerosis

    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...

  • Poly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS/FTD

    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...

  • Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial

    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.

  • ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function

    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....

  • Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS

    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...

  • Excessive release of inorganic polyphosphate by ALS/FTD astrocytes causes non-cell-autonomous toxicity to motoneurons

    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...

  • Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS

    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...

  • Imaging Net Retrograde Axonal Transport In Vivo: A Physiological Biomarker

    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.

  • Author Correction: Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

    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-Hoerth,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

  • Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

    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....

  • Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

    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...

  • Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide

    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...

  • Adaptive Platform Trials to Transform Amyotrophic Lateral Sclerosis Therapy Development

    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...

  • A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis

    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.