TY - JOUR
T1 - Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration
AU - Tsvetkov, Andrey S.
AU - Arrasate, Montserrat
AU - Barmada, Sami
AU - Ando, D. Michael
AU - Sharma, Punita
AU - Shaby, Benjamin A.
AU - Finkbeiner, Steven
PY - 2013/9
Y1 - 2013/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84883204078&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883204078&partnerID=8YFLogxK
U2 - 10.1038/nchembio.1308
DO - 10.1038/nchembio.1308
M3 - Article
C2 - 23873212
AN - SCOPUS:84883204078
SN - 1552-4450
VL - 9
SP - 586
EP - 594
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 9
ER -