期刊
ACTA NEUROPATHOLOGICA
卷 128, 期 4, 页码 505-524出版社
SPRINGER
DOI: 10.1007/s00401-014-1336-5
关键词
Amyotrophic lateral sclerosis; C9ORF72; Expanded repeat; Frontotemporal dementia; Repeat-associated non-ATG translation; Poly(GA) proteins; Proteasome activity; ER stress
资金
- National Institutes of Health/National Institute on Aging [R01 AG026251]
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [R21NS074121, R21 NS079807, R01 NS063964, R01 NS077402, R21 NS084528, P01NS084974, R01NS088689]
- National Institute of Environmental Health Services [R01 ES20395]
- Department of Defense [ALSRP AL130125]
- Mayo Clinic Foundation
- Alzheimer Association [NIRP-14-304425]
- Amyotrophic Lateral Sclerosis Association
- Robert Packard Center for ALS Research at Johns Hopkins
- Target ALS
- Canadian Institutes of Health Research
- Siragusa Foundation
- Robert and Clarice Smith & Abigail Van Buren Alzheimer's Disease Research Foundation
The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the c9RAN proteins thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.
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