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Author Notes:

Author correspondence: Thomas S. Wingo (thomas.wingo@emory.edu) or Peng Jin (peng.jin@emory.edu)

Zihui Xu and Mickael Poidevin contributed equally to this work.

T.S.W. and P.J. designed research; Z.X., M.P., X.L., Y.L., L.S., C.M.H., M.G., T.S.W., and P.J. performed research; D.L.N., H.L., T.S.W., and P.J. contributed new reagents/analytic tools; Z.X., M.P., X.L., Y.L., D.L.N., H.L., C.M.H., M.G., T.S.W., and P.J. analyzed data; and Z.X., T.S.W., and P.J. wrote the paper.

We thank the Emory Integrated Microscopy and Microanalytical Facility, members of the P.J. laboratory, and Deborah Cooper for technical assistance and C. Strauss for a critical reading of the manuscript.

This work does not represent the views of the Department of Veterans Affairs or the United States Government.

The authors declare no conflict of interest.

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Research Funding:

D.L.N. and P.J. are supported by National Institutes of Health (NIH) Grants R01 NS051630 and R21 NS067461.

P.J. is also supported by NIH Grant P50AG025688.

T.S.W. is supported by the Department of Veterans Affairs Medical Center, Atlanta, GA.

This work was supported in part by the Proteomics and Neuropathology Cores of the Emory Neuroscience National Institute of Neurological Disorders and Stroke Core Facilities (Grant P30 NS055077).

Keywords:

  • RNA-mediated neurodegeneration
  • fly model

Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration

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Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 110, Number 19

Publisher:

, Pages 7778-7783

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share phenotypic and pathologic overlap. Recently, an expansion of GGGGCC repeats in the first intron of C9orf72 was found to be a common cause of both illnesses; however, the molecular pathogenesis of this expanded repeat is unknown. Here we developed both Drosophila and mammalian models of this expanded hexanucleotide repeat and showed that expression of the expanded GGGGCC repeat RNA (rGGGGCC) is sufficient to cause neurodegeneration. We further identified Pur α as the RNA-binding protein of rGGGGCC repeats and discovered that Pur α and rGGGGCC repeats interact in vitro and in vivo in a sequence-specific fashion that is conserved between mammals and Drosophila. Furthermore, overexpression of Pur α in mouse neuronal cells and Drosophila mitigates rGGGGCC repeat-mediated neurodegeneration, and Pur α forms inclusions in the fly eye expressing expanded rGGGGCC repeats, as well as in cerebellum of human carriers of expanded GGGGCC repeats. These data suggest that expanded rGGGGCC repeats could sequester specific RNA-binding protein from their normal functions, ultimately leading to cell death. Taken together, these findings suggest that the expanded rGGGGCC repeats could cause neurodegeneration, and that Pur α may play a role in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia.

Copyright information:

© 2013 National Academy of Sciences

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