title: PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington's Disease-Associated Phenotypes In Vivo.
abstract: 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.
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Ochaba
authors.affiliation: Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Alex Mas
authors.initials: AM
authors.lastname: Monteys
authors.affiliation: Cedars-Sinai Medical Center, Board of Governors Regenerative Medicine Institute, Los Angeles, CA 90048, USA.
authors.forename: Jacqueline G
authors.initials: JG
authors.lastname: O'Rourke
authors.affiliation: Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Jack C
authors.initials: JC
authors.lastname: Reidling
authors.affiliation: Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Joan S
authors.initials: JS
authors.lastname: Steffan
authors.affiliation: Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Davidson
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA; Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: lmthomps@uci.edu.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Thompson
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics*
chemical_list: D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C106529:PIAS1 protein, human; C494211:Pias1 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D025841:Small Ubiquitin-Related Modifier Proteins