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

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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.

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Acknowledgements

We acknowledge the contributions of the Los Angeles VA Hospital (University of California Los Angeles) and the Harvard Brain Tissue Resource Center (McLean Hospital) for contributing cases to this study. 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. We would also like to acknowledge Beth Dombroski, and EunRan Suh for their assistance, and the patients and families without which this research would not be possible.

Author information

Author notes

  1. Christopher P. Cali, Maribel Patino and Yee Kit Tai contributed equally to this work.

  2. Hans Kretzschmar: Deceased.

Authors and Affiliations

  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

    Christopher P. Cali, Maribel Patino & Edward B. Lee

  2. Department of Physiology, National University of Singapore, Singapore, Singapore

    Yee Kit Tai, Wan Yun Ho & Shuo-Chien Ling

  3. Department of Anatomical Pathology, Alfred Health and Victorian Brain Bank, Florey Neurosciences, Parkville, VIC, Australia

    Catriona A. McLean

  4. Newcastle Brain Tissue Resource, Edwardson Building, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK

    Christopher M. Morris

  5. Department of Neurology, University of California, San Francisco, CA, USA

    William W. Seeley & Bruce L. Miller

  6. Department of Pathology, University of California, San Francisco, CA, USA

    William W. Seeley

  7. Universitat de Barcelona Hospital Clínic and Banc de Teixits Neurològics, Barcelona, Spain

    Carles Gaig

  8. Columbia University, NY Brain Bank, New York, NY, USA

    Jean Paul G. Vonsattel

  9. University of Texas Southwestern Medical Center, Dallas, TX, USA

    Charles L. White III

  10. Institute for Neuropathology and Prion Research and Brain Net Germany, Ludwig-Maximilians-Universität, Munich, Germany

    Sigrun Roeber & Hans Kretzschmar

  11. Department of Pathology, Johns Hopkins University, Baltimore, MD, USA

    Juan C. Troncoso

  12. London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Claire Troakes

  13. Department of Pathology, Emory University, Atlanta, GA, USA

    Marla Gearing

  14. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Bernardino Ghetti

  15. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Vivianna M. Van Deerlin, Virginia M.-Y. Lee & John Q. Trojanowski

  16. Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, UK

    Kin Y. Mok

  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

    Kin Y. Mok

  18. Reta Lila Weston Institute of Neurological Studies, University College London Institute of Neurology, London, UK

    Helen Ling

  19. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Dennis W. Dickson

  20. Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Gerard D. Schellenberg

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  1. Christopher P. Cali
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Contributions

EBL and S-CL conceived and designed this study. CPC performed RNA and protein expression experiments in patient brain and iPSCs. MP performed repeat size and risk allele genotyping. YKT, WYH and S-CL performed C9orf72 overexpression autophagy experiments. FH, WT, CMM, WWS, BLM, CG, JPGV, CLW, FMB, SR, HK, JCT, CT, MD, BG, VMVD, VMYL, JQT, KYM, HL, DWD, and GDS performed neuropathology analysis and provided DNA samples. CPC and EBL wrote the manuscript and all authors approved the final manuscript.

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Correspondence to Edward B. Lee.

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Cali, C.P., Patino, M., Tai, Y.K. et al. C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy. Acta Neuropathol 138, 795–811 (2019). https://doi.org/10.1007/s00401-019-02045-5

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