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- W3088979438 endingPage "105092" @default.
- W3088979438 startingPage "105092" @default.
- W3088979438 abstract "Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in exon 1 of the huntingtin gene. Emerging evidence shows that additional epigenetic factors can modify disease phenotypes. Harnessing the ability of the epigenome to modify the disease for therapeutic purposes is therefore of interest. Epigenome modifiers, such as histone deacetylase inhibitors (HDACi), have improved pathology in a range of HD models. Yet in clinical trials, HDACi have failed to alleviate HD symptoms in patients. This study investigated potential reasons for the lack of translation of the therapeutic benefits of HDACi from lab to clinic. We analysed histone acetylation patterns of immuno-positive nuclei from brain sections and tissue microarrays from post-mortem human control and HD cases alongside several well-established HD models (OVT73 transgenic HD sheep, YAC128 mice, and an in vitro cell model expressing 97Q mutant huntingtin). Significant increases in histone H4 acetylation were observed in post-mortem HD cases, OVT73 transgenic HD sheep and in vitro models; these changes were absent in YAC128 mice. In addition, nuclear labelling for acetyl-histone H4 levels were inversely proportional to mutant huntingtin aggregate load in HD human cortex. Our data raise concerns regarding the utility of HDACi for the treatment of HD when regions of pathology exhibit already elevated histone acetylation patterns and emphasize the importance of searching for alternative epigenetic targets in future therapeutic strategies aiming to rescue HD phenotypes." @default.
- W3088979438 created "2020-10-01" @default.
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- W3088979438 date "2020-12-01" @default.
- W3088979438 modified "2023-10-08" @default.
- W3088979438 title "Inconsistencies in histone acetylation patterns among different HD model systems and HD post-mortem brains" @default.
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- W3088979438 doi "https://doi.org/10.1016/j.nbd.2020.105092" @default.
- W3088979438 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/32979507" @default.
- W3088979438 hasPublicationYear "2020" @default.
- W3088979438 type Work @default.