ATXN1 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 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.

Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics

“…The protein encoded by the ATXN3 gene contains CAG repeats in the coding region, and the expansion of these repeats from the normal range of 13-36 to 68-79 is the cause of Machado-Joseph disease (Kawaguchi et al, 1994), also known as SCA type 3 (SCA3). Intermediate expansions of an identical repeat within ATXN1 or ATXN2 have been associated with an increased risk of ALS (Conforti et al, 2012;Tazelaar et al, 2020). However, ATXN3 repeat expansions were not shown to have the same effect (Gispert et al, 2012).…”

Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

“…This indicates that the level of TDP-43 must be tightly regulated throughout life. GOF experiments also revealed that excess of TBPH or TDP-43 is highly toxic in muscles [ 270 , 306 , 307 ], glial cells [ 270 , 307 , 309 , 325 , 326 ], and in the eye [ 266 , 274 , 289 , 290 , 292 , 293 , 302 , 303 , 304 , 306 , 307 , 310 , 312 , 314 , 315 , 316 , 317 , 318 , 319 , 320 , 324 , 327 , 328 , 329 , 330 , 331 , 332 , 333 , 334 ]. Moreover, it was reported that TBPH or TDP-43 overexpression induces cell death, as was shown in motoneurons [ 266 , 289 , 290 , 301 ], glial cells [ 309 , 326 ], mushroom bodies [ 265 , 290 ], and in the eye.…”

Whole genome sequencing for diagnosis of neurological repeat expansion disorders

“…These results are consistent with other studies showing a high concordance between WGS and PCR quantification of repeat lengths smaller than the sequencing read length. 12,13,16 The benchmark dataset included large expansions in FMR1 , DMPK , C9orf72, and FXN which can extend to up to 5 kb in size. EH was able to correctly identify expanded alleles at these loci ( Table S5 ), although EH size estimates trended lower as repeat size increased within the pathogenic range ( Figure 2, Table S7) , and this affected the ability to distinguish between large and small expansions in DMPK or between full-expansions and premutations in FMR1 ( Table S7 ).…”