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

Emmanuel Roze^*,, Sandrine Betuing^*, Carole Deyts^*, Estelle Marcon^*, Karen Brami-Cherrier, Christiane Pagès^*, Sandrine Humbert, Karine Mérienne^|| and Jocelyne Caboche^*,1

^* Université Pierre et Marie Curie-Paris 6, CNRS, UMR 7102, Paris, France;

Service de Neurologie, Hôpital Saint-Antoine, Assitance Publique-Hôpitaux de Paris, Paris, France;

Université Pierre et Marie Curie-Paris 6, INSERM, UMRS 839, Paris, France;

Institut Curie, CNRS, UMR 146,Orsay, France; and

^|| Institut de Génétique et de Biologie Moléculaire et Cellulaire, Département de pathologie moléculaire; INSERM, U596; CNRS, UMR 7104, Illkirch, France

¹Correspondence: Université Pierre et Marie Curie-Paris 6, CNRS, UMR 7102, 9 quai St. Bernard, 75005, Paris, France. E-mail: jocelyne.caboche{at}snv.jussieu.fr

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.

Key Words: Huntington’s disease • polyglutamine • histone modifications • nucleosomal response • c-Fos