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HD InsightsFinding balance in HD: The role of PIAS1 in protein homeostasis

Figure. The biochemistry in our brains is in a constant balance. In neurodegenerative disease, the scales often tilt toward a dysfunctional state. By restoring the fine balance of levels of PIAS1 in a mouse model of HD, we showed not only improvements in behavioral deficits, but a restoration of balance in several pathways known to be out of balance in HD. Decreasing the burden of PIAS1 on the cell appears to cause a shift in cellular homeostasis toward a protective state. This study suggests that PIAS1 and other E3 SUMO ligases may be key to tipping the balance between normal protein homeostasis and disease processes that cause neurodegeneration.

By: Joseph Ochaba, PhD
There are currently no medications or treatments to alter the devastating course of HD. Although some medications to ameliorate HD symptoms exist, they are often of limited effectiveness;1 therefore, there is a great need to develop treatments and discover targets to effectively alter the course of HD. As in many other neurodegenerative diseases, the underlying pathology of HD involves the decline or loss of protein quality control networks, homeostasis, and the consequent accumulation of highly insoluble protein complexes that in the case of HD contain modified and misfolded mHTT protein and other post-translationally modified proteins.

Previous studies in the lab demonstrated that the enzyme PIAS1 (an E3 SUMO-protein ligase) alters mHTT accumulation and SUMO modification of HTT in cells.2 In collaboration with Dr. Beverly Davidson’s group at the Children’s Hospital of Philadelphia, our lab recently investigated the role of PIAS1 as a potential new therapeutic target for HD in an animal model of the disease.
To examine its role in HD pathology, PIAS1 expression levels were modulated in the striatum of a rapidly progressing HD mouse model, R6/2.3 Using miRNA to knock down PIAS1 expression in the striatum, we found significant improvements in HD-associated phenotypes in a battery of motor and neuromuscular tasks; reduced pathogenic accumulation of insoluble mHTT; and improved longevity of the mice, with reduced levels of PIAS1 compared to controls.

Strikingly, reduced PIAS1 levels ameliorated neuroinflammatory disease – associated increases in apparent microglial accumulation and dysregulation of relevant proinflammatory cytokines. Conversely, overexpression of PIAS1 exacerbated disease phenotypes and the accumulation/aggregation profile. While the exact contribution of PIAS1 in HD remains unclear, we have demonstrated that this particular enzyme may provide a new target for RNAi-mediated suppression to treat several aspects of HD, including reversing protein aggregation; increasing synapses; and reducing inflammation – all of which contribute to maintaining a delicate biological balance – while also slowing or perhaps reversing behavioral decline.

While aberrant neuronal signaling, inflammation, energy production, and gene expression underlie the molecular basis of HD, a delicate balance of functional properties of the proteome ultimately dictates cell function.4,5 Under normal conditions, proteome integrity is maintained by the proteostasis network. In HD, chronic expression of expanded polyglutamine peptides results in an age-dependent collapse of this balance as evidenced by increased aggregation and mislocalization and dysfunction of stable proteins.6 Because many of these networks may be potential therapeutic targets, our current work aims to investigate more longitudinal approaches by assessing the effects of PIAS1 modulation and mHTT accumulation/aggregation dynamics in long-term mouse models of the disease, in addition to clinically relevant human patient – derived induced pluripotent stem cell neuronal subtypes, in order to fully understand the contribution of PIAS1 to HD and evaluate its potential as a clinical target. The cellular environment plays a significant role in determining whether disease proteins are converted into toxic or benign forms, and for this reason, understanding the role that PIAS1 plays pre- or post-symptomatically will be important moving forward.

Our results strengthen the link between accumulation of insoluble protein complexes and HD pathogenesis, and suggest that PIAS1 protein is a potential new target for future therapies in HD. Together, the fundamental properties identified here may also broadly impact other diseases, suggesting that regulating multifunctional proteins such as PIAS1 may be one key to tipping the balance between normal protein homeostasis and disease processes that cause neurodegeneration.


  1. Frank S. Treatment of Huntington’s disease. Neurotherapeutics. 2014 Jan;11(1):153-60. doi: 10.1007/s13311-013-0244-z.
  2. O’Rourke JG, Gareau JR, Ochaba J, et al. SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep. 2013 Jul 25;4(2):362-75. doi: 10.1016/j.celrep.2013.06.034. Epub 2013 Jul 18
  3. Ochaba J, Monteys AM, O’Rourke JG, et al. 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
  4. Tsvetkov AS, Arrasate M, Barmada S, et al. Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration. Nat Chem Biol. 2013 Sep;9(9):586-92. doi: 10.1038/nchembio.1308. Epub 2013 Jul 21
  5. Reiner A, Dragatsis I, Dietrich P. Genetics and neuropathology of Huntington’s disease. Int Rev Neurobiol. 2011; 98: 325–372. doi:  10.1016/B978-0-12-381328-2.00014-6
  6. Margulis J, Finkbeiner S. Proteostasis in striatal cells and selective neurodegeneration in Huntington’s disease. Front Cell Neurosci. 2014 Aug 7;8:218. doi: 10.3389/fncel.2014.00218. eCollection 2014.

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