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

Joseph Ochaba; Alex Mas Monteys; Jacqueline G O'Rourke; Jack C Reidling; Joan S Steffan; Beverly L Davidson; Leslie M Thompson

doi:10.1016/j.neuron.2016.03.016

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

Neuron. 2016 May 4;90(3):507-20. doi: 10.1016/j.neuron.2016.03.016. Epub 2016 Apr 14.

Authors

Joseph Ochaba¹, Alex Mas Monteys², Jacqueline G O'Rourke³, Jack C Reidling⁴, Joan S Steffan⁵, Beverly L Davidson⁶, Leslie M Thompson⁷

Affiliations

¹ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
² Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ Cedars-Sinai Medical Center, Board of Governors Regenerative Medicine Institute, Los Angeles, CA 90048, USA.
⁴ Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
⁵ 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.
⁶ 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.
⁷ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / metabolism*
Disease Models, Animal
Humans
Huntingtin Protein / genetics
Huntington Disease / genetics*
Mice
Mutation / genetics*
Nerve Tissue Proteins / genetics*
Nerve Tissue Proteins / metabolism
Neurons / metabolism*
Nuclear Proteins / metabolism
Phenotype
Protein Inhibitors of Activated STAT / genetics*
Small Ubiquitin-Related Modifier Proteins / genetics*

Substances

Huntingtin Protein
Nerve Tissue Proteins
Nuclear Proteins
PIAS1 protein, human
Pias1 protein, mouse
Protein Inhibitors of Activated STAT
Small Ubiquitin-Related Modifier Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding