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Mitogen‐ and stress‐activated protein kinase‐1 deficiency is involved in expanded‐huntingtin‐induced transcriptional dysregulation and striatal death
Author(s) -
Roze Emmanuel,
Bettuing Sandrine,
Deyts Carole,
Marcon Estelle,
BramiCherrier Karen,
Pagès Christiane,
Humbert Sandrine,
Mérienne Karine,
Caboche Jocelyne
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-9814
Subject(s) - huntingtin , neurodegeneration , mapk/erk pathway , protein kinase a , kinase , phosphorylation , microbiology and biotechnology , creb , striatum , biology , transcription factor , huntington's disease , chemistry , medicine , endocrinology , gene , biochemistry , disease , dopamine
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., Pages, C., Humbert, S., Mérienne, K., Caboche J. Mitogen‐ and stress‐activated protein kinase‐1 deficiency is involved in expanded‐hunting‐tin‐induced transcriptional dysregulation and striatal death. FASEB J. 22, 1083–1093 (2008)