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

• Type of Material: Article
• Authors: Christopher P. Cali, University of Pennsylvania; Maribel Patino, University of Pennsylvania; Yee Kit Tai, National University of Singapore; Wan Yun Ho, National University of Singapore; Catriona A. McLean, Alfred Hlth & Victorian Brain Bank; Christopher M. Morris, Newcastle University; William W. Seeley, University of California San Francisco; Bruce L. Miller, University of California San Francisco; Carles Gaig, University of Barcelona; Jean Paul G. Vonsattel, Columbia University; Charles L. White, III, University of Texas Southwestern; Sigrun Roeber, Ludwig Maximilians University Munchen; Hans Kretzschmar, Ludwig Maximilians University Munchen; Juan C. Troncoso, Johns Hopkins University; Claire Troakes, Kings College London; Marla Gearing, Emory University; Bernardino Ghetti, Indiana University; Vivianna M. Van Deerlin, University of Pennsylvania; Virginia M-Y Lee, University of Pennsylvania; John Q. Trojanowski, University of Pennsylvania; Kin Y. Mok, University College London; Helen Ling, University College London; Dennis W. Dickson, Mayo Clinic; Gerard D. Schellenberg, University of Pennsylvania; Shuo-Chien Ling, National University of Singapore; Edward B. Lee, University of Pennsylvania
• Language: English
• Date: 2019-11-01
• Publisher: SPRINGER
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Terms of use and reuse: academic research for non-commercial purposes
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s00401-019-02045-5
• Title of Journal or Parent Work: ACTA NEUROPATHOLOGICA
• Volume: 138
• Issue: 5
• Start Page: 795
• End Page: 811
• Grant/Funding Information: This study was supported by grants from the NIH (R01 NS095793, E.B.L.; R25 GM071745, M.P.; P01 AG017586, E.B.L., V.M.V.D, V.M.-Y.L, J.Q.T., G.S.; P30 AG010124, E.B.L., V.M.V.D, V.M.-Y.L, J.Q.T.; P30 AG10133, B.G.; UG3 NS104095, D.W.D.; U54 NS100693, D.W.D., G.S.; P30 AG012300 C.L.W.; P50 AG023501 and P01 AG019724 W.W.S., B.L.M.; P50 NS038377 and P50 AG05146 J.C.T.; P50 AG025688 M.G.), CurePSP (D.W.D.), the Tau Consortium (D.W.D. and W.W.S.), CBD Solutions (H.L. and K.Y.M.), National Medical Research Council, Singapore (NMRC/OFIRG/0001/2016 and NMRC/OFIRG/0042/2017 to S.C.L.), Ministry of Education, Singapore (MOE2016-T2–1-024 to S.C.L), the Reta Lila Weston Trust (K.Y.M.), the Bluefield Project to Cure FTD (W.W.S.), the UK Medical Research Council (G0400074 to C.M.M.), NIHR Newcastle Biomedical Research Center (C.M.M.), the Alzheimer’s Society and Alzheimer’s Research UK as part of the Brains for Dementia Research project (C.M.M.). The London Neurodegenerative Diseases Brain Bank receives funding from the UK Medical Research Council (MR/L016397/1) and as part of the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK and the Alzheimer’s Society.
• Keywords: Autophagy; Life Sciences & Biomedicine; PROTEIN; Science & Technology; GGGGCC-HEXANUCLEOTIDE REPEAT; Parkinsonism; Pathology; PARKINSONS-DISEASE; HYPERMETHYLATION; C9orf72 repeat expansion; Neurosciences; FRONTOTEMPORAL DEMENTIA; ALS; IDENTIFICATION; GENETIC CAUSE; Clinical Neurology; LATERAL-SCLEROSIS; Corticobasal degeneration; Neurosciences & Neurology; EXPANSION; Neurodegeneration
• Research Categories: Biology, Genetics; Health Sciences, Pathology; Biology, Neuroscience

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.