Mitogen- and stress-activated protein kinase-1 deficiency is involved in expanded-huntingtin-induced transcriptional dysregulation and striatal death

• Published in: The FASEB journal 2008-04, Vol.22 (4), p.1083-1093
• Main Authors: Roze, Emmanuel, Betuing, Sandrine, Deyts, Carole, Marcon, Estelle, Brami-Cherrier, Karen, Pagès, Christiane, Humbert, Sandrine, Mérienne, Karine, Caboche, Jocelyne
• Format: Article
• Language: English
• Subjects: Animals; Cognitive science; Corpus Striatum - enzymology; Corpus Striatum - metabolism; c‐Fos; DNA Repeat Expansion; Down-Regulation; Genes, fos; histone modifications; Histones - metabolism; Huntingtin Protein; Huntington Disease - enzymology; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington's disease; Life Sciences; Mice; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons and Cognition; Neuroscience; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; nucleosomal response; Phosphorylation; polyglutamine; Ribosomal Protein S6 Kinases, 90-kDa - deficiency; Ribosomal Protein S6 Kinases, 90-kDa - genetics; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; Transcription, Genetic
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.07-9814

Huntington's disease (HD) is a neurodegenerative disorder due to an abnormal polyglutamine expansion in the N-terminal region of huntingtin protein (Exp-Htt). This expansion causes protein aggregation and neuronal dysfunction and death. Transcriptional dysregulation due to Exp-Htt participates in neuronal death in HD. Here, using the R6/2 transgenic mouse model of HD, we identified a new molecular alteration that could account for gene dysregulation in these mice. Despite a nuclear activation of the mitogen-activated protein kinase/extracellular regulated kinase (ERK) along with Elk-1 and cAMP responsive element binding, two transcription factors involved in c-Fos transcription, we failed to detect any histone H3 phosphorylation, which is expected after nuclear ERK activation. Accordingly, we found in the striatum of these mice a deficiency of mitogen- and stress-activated kinase-1 (MSK-1), a kinase downstream ERK, critically involved in H3 phosphorylation and c-Fos induction. We extended this observation to Exp-Htt-expressing striatal neurons and postmortem brains of HD patients. In vitro, knocking out MSK-1 expression potentiated Exp-Htt-induced striatal death. Its overexpression induced H3 phosphorylation and c-Fos expression and totally protected against striatal neurodegeneration induced by Exp-Htt. We propose that MSK-1 deficiency is involved in transcriptional dysregulation and striatal degeneration. Restoration of its expression and activity may be a new therapeutic target in HD.-- Roze, E., Betuing, S., Deyts, C., Marcon, E., Brami-Cherrier, K., Pagès, C., Humbert, S., Mérienne, K., Caboche, J. Mitogen- and stress-activated protein kinase-1 deficiency is involved in expanded-huntingtin-induced transcriptional dysregulation and striatal death.