Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration

Andrey S. Tsvetkov, Montserrat Arrasate, Sami Barmada, D. Michael Ando, Punita Sharma, Benjamin A. Shaby, Steven Finkbeiner

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)586-594
Number of pages9
JournalNature Chemical Biology
Volume9
Issue number9
DOIs
StatePublished - Sep 2013

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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