title: Mitogen- and stress-activated protein kinase 1-induced neuroprotection in Huntington's disease: role on chromatin remodeling at the PGC-1-alpha promoter.
abstract: 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.
authors.affiliation: Laboratoire de Physiopathologie des Maladies du Système Nerveux central, UMR CNRS-7224 et UMRS-INSERM952, Université Pierre et Marie Curie-Paris 6, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Martin
authors.forename: Sandrine
authors.initials: S
authors.lastname: Betuing
authors.forename: Christiane
authors.initials: C
authors.lastname: Pagès
authors.forename: Karine
authors.initials: K
authors.lastname: Cambon
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Auregan
authors.forename: Nicole
authors.initials: N
authors.lastname: Deglon
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Roze
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Caboche
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects* / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D003342:Corpus Striatum / Q000378:metabolism*; D042622:DNA Repeat Expansion / Q000235:genetics; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism*; D007150:Immunohistochemistry; D016086:Lentivirus; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; C497930:Ppp1r1b protein, rat; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1