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. White, Sigrun Roeber, Hans Kretzschmar, Juan C. Troncoso, Claire Troakes, Marla Gearing, Bernardino Ghetti, Vivianna M. Van Deerlin, Virginia M.Y. Lee, John Q. TrojanowskiKin Y. Mok, Helen Ling, Dennis W. Dickson, Gerard D. Schellenberg, Shuo Chien Ling, Edward B. Lee

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)795-811
Number of pages17
JournalActa neuropathologica
Volume138
Issue number5
DOIs
StatePublished - Nov 1 2019

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Autophagy
Amyotrophic Lateral Sclerosis
Neurodegenerative Diseases
Autopsy
Clustered Regularly Interspaced Short Palindromic Repeats
tau Proteins
Dipeptides
Starvation
Microsatellite Repeats
Parkinson Disease
Stem Cells
Odds Ratio
RNA
Pathology
Gene Expression
Food
Brain
Therapeutics
Protein Aggregates

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

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

In: Acta neuropathologica, Vol. 138, No. 5, 01.11.2019, p. 795-811.

Research output: Contribution to journalArticle

Cali, CP, Patino, M, Tai, YK, Ho, WY, McLean, CA, Morris, CM, Seeley, WW, Miller, BL, Gaig, C, Vonsattel, JPG, White, CL, Roeber, S, Kretzschmar, H, Troncoso, JC, Troakes, C, Gearing, M, Ghetti, B, Van Deerlin, VM, Lee, VMY, Trojanowski, JQ, Mok, KY, Ling, H, Dickson, DW, Schellenberg, GD, Ling, SC & Lee, EB 2019, 'C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy', Acta neuropathologica, vol. 138, no. 5, pp. 795-811. https://doi.org/10.1007/s00401-019-02045-5
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. / C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy. In: Acta neuropathologica. 2019 ; Vol. 138, No. 5. pp. 795-811.
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AU - Cali, Christopher P.

AU - Patino, Maribel

AU - Tai, Yee Kit

AU - Ho, Wan Yun

AU - McLean, Catriona A.

AU - Morris, Christopher M.

AU - Seeley, William W.

AU - Miller, Bruce L.

AU - Gaig, Carles

AU - Vonsattel, Jean Paul G.

AU - White, Charles L.

AU - Roeber, Sigrun

AU - Kretzschmar, Hans

AU - Troncoso, Juan C.

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AU - Gearing, Marla

AU - Ghetti, Bernardino

AU - Van Deerlin, Vivianna M.

AU - Lee, Virginia M.Y.

AU - Trojanowski, John Q.

AU - Mok, Kin Y.

AU - Ling, Helen

AU - Dickson, Dennis W.

AU - Schellenberg, Gerard D.

AU - Ling, Shuo Chien

AU - Lee, Edward B.

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