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 polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P = 3.33 × 10-7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.

Original languageEnglish
Article numberfcaa064
JournalBrain Communications
Issue number2
StatePublished - 2020


FundersFunder number
American ALS Association
Association pour la Recherche sur la Sclérose
Dutch ALS Foundation
European Community's Health Seventh Framework Programme
Inan Kirac Foundation
MND Association of England, Wales and Northern Ireland
Rudolf Magnus Brain Center
National Institutes of Health
National Institute of Neurological Disorders and StrokeR01NS073873
ALS Association
European Molecular Biology Organization
Association Française contre les Myopathies
Fondation Thierry Latran
South London and Maudsley NHS Foundation Trust
Wellcome Trust
Health Research Board
Seventh Framework Programme
EU Joint Programme – Neurodegenerative Disease Research
Sophia University
Medical Research CouncilMR/R024804/1, MR/L501529/1
Economic and Social Research CouncilES/L008238/1
National Institute for Health and Care Research
Motor Neurone Disease Association
King's College London
European Research Council
Agentschap voor Innovatie door Wetenschap en Technologie
Horizon 2020772376-EScORIAL
Vlaamse regering


    • DNA repeat expansion
    • amyotrophic lateral sclerosis
    • genetic association study
    • trinucleotide repeat expansions


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