| First Author | Martin E | Year | 2011 |
| Journal | Hum Mol Genet | Volume | 20 |
| Issue | 12 | Pages | 2422-34 |
| PubMed ID | 21493629 | Mgi Jnum | J:172062 |
| Mgi Id | MGI:5003383 | Doi | 10.1093/hmg/ddr148 |
| Citation | Martin E, et al. (2011) Mitogen- and stress-activated protein kinase 1-induced neuroprotection in Huntington's disease: role on chromatin remodeling at the PGC-1-alpha promoter. Hum Mol Genet 20(12):2422-34 |
| abstractText | 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 gamma coactivator alpha (PGC-1alpha), a transcriptional co-activator involved in mitochondrial biogenesis. Chromatin immunoprecipitation indicated that transcriptional regulation of PGC-1alpha is directly linked to increased binding of MSK-1, along with H3 and CREB phosphorylation of the PGC-1alpha 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-1alpha expression. Strategies aimed at restoring MSK-1 expression in the striatum might offer a new therapeutic approach to HD. |
