Details

Autor(en) / Beteiligte

• Ochaba, Joseph
• Monteys, Alex Mas
• O’Rourke, Jacqueline G.
• Reidling, Jack C.
• Steffan, Joan S.
• Davidson, Beverly L.
• Thompson, Leslie M.

Titel

PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington’s Disease-Associated Phenotypes In Vivo

Ist Teil von

• Neuron (Cambridge, Mass.), 2016-05, Vol.90 (3), p.507-520

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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. •Reducing PIAS1 levels rescues mHTT-associated phenotypes in R6/2 mice•Striatal modulation of PIAS1 alters insoluble mHTT, SUMO, and ubiquitin accumulation•PIAS1 reduction normalizes inflammatory homeostasis of key markers in R6/2 striatum•PIAS1 overexpression exacerbates mHTT-associated phenotypes Ochaba et al. find that PIAS1, when reduced in R6/2 mice, is protective and significantly restores dysfunctional pathways associated with pathogenesis by decreasing aberrant mutant Huntingtin accumulation. This novel therapeutic target may therefore act as an important regulatory switch.