期刊
NEURON
卷 88, 期 4, 页码 667-677出版社
CELL PRESS
DOI: 10.1016/j.neuron.2015.10.038
关键词
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资金
- CHDI Foundation, Inc.
- W.F. Keck Foundation
- University of Florida
- Sara Borrell contract from the Spanish Ministry of Health, ISCIII
- University of Florida Alumni Fellowship
- NIH [NS082168]
- John Hopkins University Alzheimer's Disease Research Center [NIH P50AG05146]
Huntington disease (HD) is caused by a CAG, CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGlnexpansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open reading frame and suggests RAN translation may also contribute to other polyglutamine diseases.
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