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Acta Neuropathologica

, Volume 138, Issue 5, pp 795–811 | Cite as

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

  • Christopher P. Cali
  • Maribel Patino
  • Yee Kit Tai
  • Wan Yun Ho
  • Catriona A. McLean
  • Christopher M. Morris
  • William W. Seeley
  • Bruce L. Miller
  • Carles Gaig
  • Jean Paul G. Vonsattel
  • Charles L. WhiteIII
  • Sigrun Roeber
  • Hans Kretzschmar
  • Juan C. Troncoso
  • Claire Troakes
  • Marla Gearing
  • Bernardino Ghetti
  • Vivianna M. Van Deerlin
  • Virginia M.-Y. Lee
  • John Q. Trojanowski
  • Kin Y. Mok
  • Helen Ling
  • Dennis W. Dickson
  • Gerard D. Schellenberg
  • Shuo-Chien Ling
  • Edward B. LeeEmail author
Original Paper

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

Neurodegeneration Corticobasal degeneration C9orf72 repeat expansion Parkinsonism Autophagy 

Notes

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 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.

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.

Supplementary material

401_2019_2045_MOESM1_ESM.pdf (1.3 mb)
Supplementary material 1 (PDF 1325 kb)
401_2019_2045_MOESM2_ESM.csv (1.7 mb)
Supplementary material 2 (CSV 1699 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Christopher P. Cali
    • 1
  • Maribel Patino
    • 1
  • Yee Kit Tai
    • 2
  • Wan Yun Ho
    • 2
  • Catriona A. McLean
    • 3
  • Christopher M. Morris
    • 4
  • William W. Seeley
    • 5
    • 6
  • Bruce L. Miller
    • 5
  • Carles Gaig
    • 7
  • Jean Paul G. Vonsattel
    • 8
  • Charles L. WhiteIII
    • 9
  • Sigrun Roeber
    • 10
  • Hans Kretzschmar
    • 10
  • Juan C. Troncoso
    • 11
  • Claire Troakes
    • 12
  • Marla Gearing
    • 13
  • Bernardino Ghetti
    • 14
  • Vivianna M. Van Deerlin
    • 15
  • Virginia M.-Y. Lee
    • 15
  • John Q. Trojanowski
    • 15
  • Kin Y. Mok
    • 16
    • 17
  • Helen Ling
    • 18
  • Dennis W. Dickson
    • 19
  • Gerard D. Schellenberg
    • 20
  • Shuo-Chien Ling
    • 2
  • Edward B. Lee
    • 1
    Email author
  1. 1.Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of PhysiologyNational University of SingaporeSingaporeSingapore
  3. 3.Department of Anatomical PathologyAlfred Health and Victorian Brain Bank, Florey NeurosciencesParkvilleAustralia
  4. 4.Newcastle Brain Tissue Resource, Edwardson BuildingNewcastle UniversityNewcastle upon TyneUK
  5. 5.Department of NeurologyUniversity of CaliforniaSan FranciscoUSA
  6. 6.Department of PathologyUniversity of CaliforniaSan FranciscoUSA
  7. 7.Universitat de Barcelona Hospital Clínic and Banc de Teixits NeurològicsBarcelonaSpain
  8. 8.Columbia University, NY Brain BankNew YorkUSA
  9. 9.University of Texas Southwestern Medical CenterDallasUSA
  10. 10.Institute for Neuropathology and Prion Research and Brain Net GermanyLudwig-Maximilians-UniversitätMunichGermany
  11. 11.Department of PathologyJohns Hopkins UniversityBaltimoreUSA
  12. 12.London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonLondonUK
  13. 13.Department of PathologyEmory UniversityAtlantaUSA
  14. 14.Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisUSA
  15. 15.Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  16. 16.Department of Neurodegenerative DiseaseUniversity College London Queen Square Institute of NeurologyLondonUK
  17. 17.Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience CenterThe Hong Kong University of Science and TechnologyKowloonChina
  18. 18.Reta Lila Weston Institute of Neurological StudiesUniversity College London Institute of NeurologyLondonUK
  19. 19.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  20. 20.Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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