Article: article d'un périodique ou d'un magazine.
Mitogen- and stress-activated protein kinase 1-induced neuroprotection in Huntington's disease: role on chromatin remodeling at the PGC-1-alpha promoter.
Human Molecular Genetics
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Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Huntington's disease (HD) is a neurodegenerative disorder due to abnormal polyglutamine expansion in huntingtin protein (Exp-Htt). This expansion causes protein aggregation, leading to neuronal dysfunction and death. We have previously shown that mitogen- and stress-activated kinase (MSK-1), a nuclear protein kinase involved in chromatin remodeling through histone H3 phosphorylation, is deficient in the striatum of HD patients and model mice. Restoring MSK-1 expression in cultured striatal cells prevented neuronal dysfunction and death induced by Exp-Htt. Here we extend these observations in a rat model of HD based on striatal lentiviral expression of Exp-Htt (LV-Exp-HTT). MSK-1 overexpression attenuated Exp-Htt-induced down-regulation of DARPP-32 expression 4 and 10 weeks after infection and enhanced NeuN staining after 10 weeks. LV-MSK-1 induced constitutive hyperphosphorylation of H3 and cAMP-responsive element binding protein (CREB), indicating that MSK-1 has spontaneous catalytic activity. MSK-1 overexpression also upregulated peroxisome proliferator-activated receptor γ coactivator alpha (PGC-1α), a transcriptional co-activator involved in mitochondrial biogenesis. Chromatin immunoprecipitation indicated that transcriptional regulation of PGC-1α is directly linked to increased binding of MSK-1, along with H3 and CREB phosphorylation of the PGC-1α promoter. MSK-1 knock-out mice showed spontaneous striatal atrophy as they aged, as well as higher susceptibility to systemic administration of the mitochondrial neurotoxin 3-NP. These results indicate that MSK-1 activation is an important and key event in the signaling cascade that regulates PGC-1α expression. Strategies aimed at restoring MSK-1 expression in the striatum might offer a new therapeutic approach to HD.
Analysis of Variance, Animals, Chromatin Assembly and Disassembly/drug effects, Chromatin Assembly and Disassembly/physiology, Chromatin Immunoprecipitation, Corpus Striatum/metabolism, DNA Repeat Expansion/genetics, Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism, Gene Expression Regulation/drug effects, Gene Expression Regulation/physiology, Genetic Vectors/genetics, Huntington Disease/metabolism, Immunohistochemistry, Lentivirus, Mice, Mice, Knockout, Microscopy, Fluorescence, Nerve Tissue Proteins/genetics, Nerve Tissue Proteins/metabolism, Neuroprotective Agents/metabolism, Neuroprotective Agents/pharmacology, Nuclear Proteins/genetics, Nuclear Proteins/metabolism, Phosphorylation, Promoter Regions, Genetic/genetics, RNA-Binding Proteins/genetics, RNA-Binding Proteins/metabolism, Rats, Rats, Wistar, Ribosomal Protein S6 Kinases, 90-kDa/metabolism, Ribosomal Protein S6 Kinases, 90-kDa/pharmacology, Transcription Factors/genetics, Transcription Factors/metabolism
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