Please use this identifier to cite or link to this item: https://doi.org/10.1007/s00401-019-02045-5
Title: C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy
Authors: Cali, Christopher P
Patino, Maribel
Tai, Yee Kit 
Ho, Wan Yun 
McLean, Catriona A
Morris, Christopher M
Seeley, William W
Miller, Bruce L
Gaig, Carles
Vonsattel, Jean Paul G
White, Charles L
Roeber, Sigrun
Kretzschmar, Hans
Troncoso, Juan C
Troakes, Claire
Gearing, Marla
Ghetti, Bernardino
Van Deerlin, Vivianna M
Lee, Virginia M-Y
Trojanowski, John Q
Mok, Kin Y
Ling, Helen
Dickson, Dennis W
Schellenberg, Gerard D
Ling, Shuo-Chien 
Lee, Edward B
Keywords: Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Pathology
Neurosciences & Neurology
Neurodegeneration
Corticobasal degeneration
C9orf72 repeat expansion
Parkinsonism
Autophagy
GGGGCC-HEXANUCLEOTIDE REPEAT
FRONTOTEMPORAL DEMENTIA
PARKINSONS-DISEASE
LATERAL-SCLEROSIS
GENETIC CAUSE
EXPANSION
HYPERMETHYLATION
PROTEIN
ALS
IDENTIFICATION
Issue Date: 1-Nov-2019
Publisher: SPRINGER
Citation: Cali, Christopher P, Patino, Maribel, Tai, Yee Kit, Ho, Wan Yun, McLean, Catriona A, Morris, Christopher M, Seeley, William W, Miller, Bruce L, Gaig, Carles, Vonsattel, Jean Paul G, White, Charles L, Roeber, Sigrun, Kretzschmar, Hans, Troncoso, Juan C, Troakes, Claire, Gearing, Marla, Ghetti, Bernardino, Van Deerlin, Vivianna M, Lee, Virginia M-Y, Trojanowski, John Q, Mok, Kin Y, Ling, Helen, Dickson, Dennis W, Schellenberg, Gerard D, Ling, Shuo-Chien, Lee, Edward B (2019-11-01). C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy. ACTA NEUROPATHOLOGICA 138 (5) : 795-811. ScholarBank@NUS Repository. https://doi.org/10.1007/s00401-019-02045-5
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.
Source Title: ACTA NEUROPATHOLOGICA
URI: https://scholarbank.nus.edu.sg/handle/10635/205790
ISSN: 00016322
14320533
DOI: 10.1007/s00401-019-02045-5
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