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Acta Neuropathol. 2019 Nov;138(5):795-811. doi: 10.1007/s00401-019-02045-5. Epub 2019 Jul 20.

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

Author information

1
Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 613A Stellar Chance Laboratories, 422 Curie Blvd, Philadelphia, PA, 19104, USA.
2
Department of Physiology, National University of Singapore, Singapore, Singapore.
3
Department of Anatomical Pathology, Alfred Health and Victorian Brain Bank, Florey Neurosciences, Parkville, VIC, Australia.
4
Newcastle Brain Tissue Resource, Edwardson Building, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
5
Department of Neurology, University of California, San Francisco, CA, USA.
6
Department of Pathology, University of California, San Francisco, CA, USA.
7
Universitat de Barcelona Hospital Clínic and Banc de Teixits Neurològics, Barcelona, Spain.
8
Columbia University, NY Brain Bank, New York, NY, USA.
9
University of Texas Southwestern Medical Center, Dallas, TX, USA.
10
Institute for Neuropathology and Prion Research and Brain Net Germany, Ludwig-Maximilians-Universität, Munich, Germany.
11
Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
12
London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
13
Department of Pathology, Emory University, Atlanta, GA, USA.
14
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
15
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
16
Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, UK.
17
Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
18
Reta Lila Weston Institute of Neurological Studies, University College London Institute of Neurology, London, UK.
19
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
20
Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
21
Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 613A Stellar Chance Laboratories, 422 Curie Blvd, Philadelphia, PA, 19104, USA. edward.lee@uphs.upenn.edu.

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.

KEYWORDS:

Autophagy; C9orf72 repeat expansion; Corticobasal degeneration; Neurodegeneration; Parkinsonism

PMID:
31327044
PMCID:
PMC6802287
[Available on 2020-11-01]
DOI:
10.1007/s00401-019-02045-5

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