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

Lookup NU author(s): Dr Christopher Morris

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): Cali CP, Patino M, Tai YK, Ho WY, McLean CA, Morris CM, Seeley WW, Miller BL, Gaig C, Vonsattel JPG, White CL, Roeber S, Kretzschmar H, Troncoso JC, Troakes C, Gearing M, Ghetti B, Van Deerlin VM, Lee VM, Trojanowski JQ, Mok KY, Ling H, Dickson DW, Schellenberg GD, Ling SC, Lee EB

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica

Year: 2019

Volume: 138

Pages: 795-811

Online publication date: 20/07/2019

Acceptance date: 16/07/2019

Date deposited: 03/09/2019

ISSN (print): 0001-6322

ISSN (electronic): 1432-0533

Publisher: Springer

URL: https://doi.org/10.1007/s00401-019-02045-5

DOI: 10.1007/s00401-019-02045-5

PubMed id: 31327044


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