期刊
BRAIN COMMUNICATIONS
卷 2, 期 2, 页码 -出版社
OXFORD UNIV PRESS
DOI: 10.1093/braincomms/fcaa064
关键词
amyotrophic lateral sclerosis; trinucleotide repeat expansions; DNA repeat expansion; genetic association study
资金
- ALS Foundation Netherlands
- Belgian ALS Liga and National Lottery
- Agency for Innovation by Science and Technology (IWT)
- MND Association (UK)
- European Community's Health Seventh Framework Programme (FP7/2007-2013)
- ZonMW
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [772376-EScORIAL]
- PPP Allowance by Healthsimilar toHolland, Top Sector Life Sciences Health
- UK, Medical Research Council [MR/L501529/1, MR/R024804/1]
- UK, Economic and Social Research Council [ES/L008238/1]
- Ireland, Health Research Board
- Netherlands, ZonMw
- Belgium, FWO-Vlaanderen
- MND Association
- Wellcome Trust
- MND Association of England
- MND Association of Wales
- MND Association of Northern Ireland
- Netherlands Organisation for Health Research and Development
- Suna and Inan Kirac Foundation
- US National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) [R01NS073873]
- American ALS Association
- Thierry Latran Foundation
- Dutch ALS Foundation
- Rudolf Magnus Brain Center Talent Fellowship
- Health Research Board Clinician Scientist Programme
- Science Foundation Ireland
- Thierry Latran Foundation (ALSIBD)
- ALS Association [2284]
- ALS Liga Belgie
- Een hart voor ALS
- Laevers fund for ALS research
- Association francaise contre les myopathies (AFM)
- Association pour la Recherche sur la Sclerose laterale amyotrophique et autres maladies du motoneurone (ARSla)
- MRC [MR/R024804/1, G0600974] Funding Source: UKRI
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 x 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.
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