Our previous work has contributed to our understanding of (1) an age-dependent attenuation of the HSR, (2) small molecules that support and enhance the HSR, and (3) role of chaperones in the structuring, aggregation and pathogenicity of mHtt in cell models of Huntington\u2019s disease (HD).<\/p>\n
(1) Age-dependent and neuron specific attenuation in the HSR<\/u><\/em><\/p>\n In published work, we showed that induction of HSP chaperones by stress is compromised upon aging and particularly in neuronal cells.\u00a0\u00a0 Our observation adds to the theme that proteome quality control is central to the wellbeing of cells to safeguard against \u201cprotein conformation\u201d disease, Alzheimer\u2019s, Parkinson\u2019s, and Huntington\u2019s diseases as examples.<\/p>\n <\/p>\n (2) Identification of small molecule to enhance and support the HSR<\/u><\/em><\/p>\n Given the critical importance of maintaining the cell proteome in GOOD form, we have worked to identify small molecules and drugs that can support or enhance the activation of HSF1 to induce HSP chaperones for protein QC.\u00a0 We evaluated the effects of riluzole (the first and only FDA approved drug for the treatment of ALS) and of resveratrol, an activator of the SIRT1 deacetylase, in the regulation and function of HSF1.\u00a0\u00a0 Our studies showed that riluzole, by blunting the turnover of HSF1, increased HSF1 reserve and that resveratrol, a small molecule activator of the longevity assurance deacetylase Sirtuin 1 (SIRT1), sustained the activation of HSF1.\u00a0\u00a0 Neither riluzole nor resveratrol directly activate HSF1 but significantly enhance the effects of stress in promoting the activation of HSF1 for a more robust response.\u00a0 Both classes of drugs have been or currently are in clinical trials for various ND conditions, although such efforts have yet to translate to successful therapeutics.<\/p>\n (3) \u00a0Structuring, aggregation vis-a-vis pathogenicity of polyQ-expanded huntingtin<\/u><\/em><\/p>\n Q represents the amino acid \u201cglutamine\u201d, and a contiguous string of \u201cQ\u201d in proteins is often used as a motif for protein binding\/recognition\/signaling.\u00a0 PolyQ expansion of key regulatory proteins is associated with 9 different neurodegenerative diseases, with Huntington\u2019s disease (HD) being a prime example.\u00a0 PolyQ-expanded mHttexon1<\/sup> is an intrinsically disordered protein (IDP), and in cells it assumes a variety of conformations and can aggregate to form \u201cinclusion bodies\u201d.\u00a0 A long unresolved question in HD is \u201cwhich of these mHtt conformers is pathogenic?\u201d\u00a0 This is an critically important issue with significant implications in framing therapeutics development for HD.\u00a0 In our recent studies, we showed that conditions that promote protein structuring \u2013 including the increased expression of HSP chaperones or the addition of osmolytes – promote the aggregation of mHtt to form inclusion body (IB) and alleviates transcription factor dysfunction to promote neuron survival. Our work along with a string of observations from other laboratories suggest that it is primarily the low molecular weight entities of mHtt that drives HD pathogenesis.<\/p>\n\n
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