期刊
NATURE CHEMICAL BIOLOGY
卷 9, 期 9, 页码 586-U91出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1308
关键词
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资金
- US National Institute of Neurological Disease and Stroke [R01 3NS039746, 2R01 NS045191]
- National Institute on Aging [P01 2AG022074]
- Huntington's Disease Society of America
- Taube-Koret Center for Neurodegenerative disease
- Gladstone Institutes
- Hereditary Disease Foundation
- Hillblom Foundation
- California Institute for Regenerative Medicine
- US National Science Foundation [DMS-0914906]
- US National Center for Research Resources [RR18928-01]
- US National Institutes of Health Extramural Research Facilities Improvement Project [C06 RR018928]
In polyglutamine (polyQ) diseases, only certain neurons die, despite widespread expression of the offending protein. PolyQ expansion may induce neurodegeneration by impairing proteostasis, but protein aggregation and toxicity tend to confound conventional measurements of protein stability. Here, we used optical pulse labeling to measure effects of polyQ expansions on the mean lifetime of a fragment of huntingtin, the protein that causes Huntington's disease, in living neurons. We show that polyQ expansion reduced the mean lifetime of mutant huntingtin within a given neuron and that the mean lifetime varied among neurons, indicating differences in their capacity to clear the polypeptide. We found that neuronal longevity is predicted by the mean lifetime of huntingtin, as cortical neurons cleared mutant huntingtin faster and lived longer than striatal neurons. Thus, cell type-specific differences in turnover capacity may contribute to cellular susceptibility to toxic proteins, and efforts to bolster proteostasis in Huntington's disease, such as protein clearance, could be neuroprotective.
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