B16 Mitogen And Stress-activated Kinase-1 Deficiency And Transcriptional Dysregulation In Huntington's Disease

• Published in: Journal of neurology, neurosurgery and psychiatry Vol. 85; no. Suppl 1; p. A14
• Main Authors: Moumne, L., Brami-Cherrier, K., Betuing, S., Le Crom, S., Girault, J., Caboche, J.
• Format: Journal Article
• Language: English
• Published: BMJ Publishing Group 01.09.2014
• Subjects: Life Sciences; Neurons and Cognition
• ISSN: 0022-3050; 1468-330X
• DOI: 10.1136/jnnp-2014-309032.44

Transcriptional dysregulation has emerged as a pathogenic process that appears early in Huntington’s disease (HD) progression and has been recapitulated across multiple HD models. We have been studying the involvement of the Mitogen and Stress-activated Kinase-1 (MSK-1) in transcriptional dysregulation in HD. This striatum-enriched protein kinase acts on chromatin remodelling through histone H3 phosphorylation leading to transcriptional activation. MSK-1 plays a dual role in gene transcription since it also activates the transcription factor cAMP-responsive element binding protein (CREB) in the striatum. We have previously shown that MSK-1 expression is reduced in the striatum of HD patients and model mice. Its overexpression in primary striatal cells as well as in a rat model of HD prevents neuronal dysfunction and death induced by Exp-HTT. To understand the mechanism by which MSK-1 exerts its neuroprotective effect in the striatum it is important to identify its molecular targets. For this purpose we compared the expression of striatal genes between MSK-1 knock-out and wild type mice using a whole transcriptome shotgun sequencing. Among the genes dysregulated in MSK-1 KO mice, we identified genes involved in several cellular processes including oxidative or excitotoxic stress protection. Expression study of a set of these genes by quantitative RT-PCR showed that most of them are dysregulated in a cellular model (STHdh-Q111) and a mouse model (R6/2) of HD. These results suggest that MSK-1 down-regulation in HD is responsible for part of the transcription dysregulation observed in this disease and that restoring its expression could lead to reversion of these dysregulations.