C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy.

TitleC9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy.
Publication TypeJournal Article
Year of Publication2019
AuthorsCali CP, Patino M, Tai YKit, Ho WYun, McLean CA, Morris CM, Seeley WW, Miller BL, Gaig C, Vonsattel JPaul G, White CL, Roeber S, Kretzschmar H, Troncoso JC, Troakes C, Gearing M, Ghetti B, Van Deerlin VM, Lee VM-Y, Trojanowski JQ, Mok KY, Ling H, Dickson DW, Schellenberg GD, Ling S-C, Lee EB
JournalActa Neuropathol
Volume138
Issue5
Pagination795-811
Date Published11/2019
ISSN1432-0533
Abstract

Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s-1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson's disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson's but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n = 354 cases, odds ratio = 3.59, p = 0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC-derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.

DOI10.1007/s00401-019-02045-5
Alternate JournalActa Neuropathol.
PubMed ID31327044
PubMed Central IDPMC6802287
Grant ListP01 AG017586 / NH / NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
P30 AG012300 / AG / NIA NIH HHS / United States
P30 AG062422 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
G0400074 / MRC_ / Medical Research Council / United Kingdom
NMRC/OFIRG/0001/2016 / / National Medical Research Council Singapore / International
U54 NS100693 / NS / NINDS NIH HHS / United States
R25 GM071745 / GM / NIGMS NIH HHS / United States
NMRC/OFIRG/0042/2017 / / National Medical Research Council Singapore / International
P30 AG010124 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
P01 AG017586 / AG / NIA NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
G0400074 / / UK Medical Research Council / International
U19 AG062418 / AG / NIA NIH HHS / United States
MR/L016397/1 / MRC_ / Medical Research Council / United Kingdom
R01 NS095793 / NS / NINDS NIH HHS / United States
P50 NS038377 / NS / NINDS NIH HHS / United States
MOE2016-T2-1-024 / / Ministry of Education Singapore / International
UG3 NS104095 / NS / NINDS NIH HHS / United States