Journal
NEURON
Volume 90, Issue 3, Pages 507-520Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2016.03.016
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Funding
- NIH [NS090390, NS52789, NS072453, NS076631]
- Hereditary Disease Foundation
- CHDI Foundation
- Roy J. Carver Trust
- Children's Hospital of Philadelphia Research Institute
- Hoppy's Hope Foundation
- Janet Westerfield Foundation
- National Science Foundation (NSF)
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The disruption of protein quality control networks is central to pathology in Huntington's disease (HD) and other neurodegenerative disorders. The aberrant accumulation of insoluble high-molecular-weight protein complexes containing the Huntingtin (HTT) protein and SUMOylated protein corresponds to disease manifestation. We previously identified an HTT-selective E3 SUMO ligase, PIAS1, that regulates HTT accumulation and SUMO modification in cells. Here we investigated whether PIAS1 modulation in neurons alters HD-associated phenotypes in vivo. Instrastriatal injection of a PIAS1-directed miRNA significantly improved behavioral phenotypes in rapidly progressing mutant HTT (mHTT) fragment R6/2 mice. PIAS1 reduction prevented the accumulation of mHTT and SUMO-and ubiquitin-modified proteins, increased synaptophysin levels, and normalized key inflammatory markers. In contrast, PIAS1 overexpression exacerbated mHTT-associated phenotypes and aberrant protein accumulation. These results confirm the association between aberrant accumulation of expanded polyglutamine-dependent insoluble protein species and pathogenesis, and they link phenotypic benefit to reduction of these species through PIAS1 modulation.
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