<i>ATXN1</i> repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization

Abstract

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 <i>C9orf72</i>, polyglutamine expansions in <i>ATXN2</i> and polyalanine expansions in <i>NIPA1</i>. 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 <i>ATXN1</i>, suggested a similar disease association for the repeat expansion in <i>ATXN1</i>. We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate <i>ATXN1</i> repeat expansions and amyotrophic lateral sclerosis (<i>P </i>=<i> </i>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 <i>Drosophila</i>, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.