期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 19, 页码 7778-7783出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1219643110
关键词
RNA-mediated neurodegeneration; fly model
资金
- National Institutes of Health (NIH) [R01 NS051630, R21 NS067461, P50AG025688]
- Department of Veterans Affairs Medical Center, Atlanta, GA
- Proteomics and Neuropathology Cores of the Emory Neuroscience National Institute of Neurological Disorders and Stroke Core Facilities [P30 NS055077]
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 a as the RNA-binding protein of rGGGGCC repeats and discovered that Pur a 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 a in mouse neuronal cells and Drosophila mitigates rGGGGCC repeat-mediated neurodegeneration, and Pur a 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 a may play a role in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia.
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