Matches in SemOpenAlex for { <https://semopenalex.org/work/W3139325159> ?p ?o ?g. }
- W3139325159 endingPage "105336" @default.
- W3139325159 startingPage "105336" @default.
- W3139325159 abstract "In Huntington's disease (HD), the mutant huntingtin (mHtt) accumulates as toxic aggregates in the striatum tissue, with deleterious effects on motor-coordination and cognitive functions. Reducing the levels of mHtt is therefore a promising therapeutic strategy. We have previously reported that GSK-3 is a negative regulator of the autophagy/lysosome pathway, which is responsible for intracellular degradation, and is critically important for maintaining neuronal vitality. Thus, we hypothesized that inhibition of GSK-3 may trigger mHtt clearance thereby reducing mHtt cytotoxicity and improving HD symptoms. Here, we demonstrate that depletion or suppression of autophagy results in a massive accumulation of mHtt aggregates. Accordingly, mHtt aggregates were localized in lysosomes, but, mostly mislocalized from lysosomes in the absence of functional autophagy. Overexpression of GSK-3, particularly the α isozyme, increased the number of mHtt aggregates, while silencing GSK-3α/β, or treatment with a selective GSK-3 inhibitor, L807mts, previously described by us, reduced the amounts of mHtt aggregates. This effect was mediated by increased autophagic and lysosomal activity. Treating R6/2 mouse model of HD with L807mts, reduced striatal mHtt aggregates and elevated autophagic and lysosomal markers. The L807mts treatment also reduced hyperglycemia and improved motor-coordination functions in these mice. In addition, L807mts restored the expression levels of Sirt1, a critical neuroprotective factor in the HD striatum, along with its targets BDNF, DRPP-32, and active Akt, all provide neurotrophic/pro-survival support and typically decline in the HD brain. Our results provide strong evidence for a role for GSK-3 in the regulation of mHtt dynamics, and demonstrate the benefits of GSK-3 inhibition in reducing mHtt toxicity, providing neuroprotective support, and improving HD symptoms." @default.
- W3139325159 created "2021-03-29" @default.
- W3139325159 creator A5026335363 @default.
- W3139325159 creator A5026567004 @default.
- W3139325159 creator A5043326293 @default.
- W3139325159 creator A5045192279 @default.
- W3139325159 creator A5054107352 @default.
- W3139325159 creator A5073598703 @default.
- W3139325159 date "2021-07-01" @default.
- W3139325159 modified "2023-09-30" @default.
- W3139325159 title "Inhibition of GSK-3 ameliorates the pathogenesis of Huntington's disease" @default.
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