title: Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration.
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.
authors.affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Taube-Koret Center for Neurodegenerative Disease Research, San Francisco, California, USA.
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Tsvetkov
authors.forename: Montserrat
authors.initials: M
authors.lastname: Arrasate
authors.forename: Sami
authors.initials: S
authors.lastname: Barmada
authors.forename: D Michael
authors.initials: DM
authors.lastname: Ando
authors.forename: Punita
authors.initials: P
authors.lastname: Sharma
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Shaby
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
mesh_terms: D006207:Half-Life; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*; D010455:Peptides / Q000378:metabolism*; D059748:Proteolysis; D057165:Proteostasis Deficiencies / Q000378:metabolism / Q000473:pathology; D019680:Trinucleotide Repeat Expansion
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine