Open AccessATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization
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,
HenkJan Westeneng,
Kevin P. Kenna,
Abdelilah Assialioui,
Nica Da Silva,
Mònica Povedano,
Jesús 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 AlChalabi,
Leonard H. van den Berg,
Philip Van Damme,
Jan H. Veldink,
Michael A. van Es
Publication year - 2020
Publication title -
brain communications
Language(s) - English
Resource type - Journals
ISSN - 2632-1297
DOI - 10.1093/braincomms/fcaa064
Subject(s) - amyotrophic lateral sclerosis , c9orf72 , spinocerebellar ataxia , trinucleotide repeat expansion , disease , neuroscience , medicine , biology , ataxia , frontotemporal dementia , genetics , pathology , gene , dementia , allele
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.