Implication of the JNK pathway in a rat model of Huntington's disease.

Détails

ID Serval
serval:BIB_A51A90FAC927
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Implication of the JNK pathway in a rat model of Huntington's disease.
Périodique
Experimental Neurology
Auteur⸱e⸱s
Perrin V., Dufour N., Raoul C., Hassig R., Brouillet E., Aebischer P., Luthi-Carter R., Déglon N.
ISSN
1090-2430 (Electronic)
ISSN-L
0014-4886
Statut éditorial
Publié
Date de publication
2009
Volume
215
Numéro
1
Pages
191-200
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Résumé
Huntington's disease (HD) is a neurodegenerative disorder resulting from the expansion of a glutamine repeat (polyQ) in the N-terminus of the huntingtin (htt) protein. Expression of polyQ-containing proteins has been previously shown to induce various cellular stress responses. Among these, activation of the c-Jun N-terminal kinase (JNK) cascade has been observed in cellular models of HD. However, the implication of the JNK pathway has not previously been evaluated in the striatum of HD animal models. Here we report that the JNK pathway participates in HD pathology in a rat model of the disease. Increased phosphorylation of the JNK target c-Jun was observed as early as 4 weeks and persisted for 13 weeks after lentiviral-mediated expression of htt171-82Q. In order to assess the importance of this pathway in HD pathology, JNK inhibitors including dominant-negative mutants of upstream kinases (ASK1(K709R), MEKK1(D1369A)), a c-Jun mutant (Delta169c-Jun) and the active domain of the scaffold protein JIP-1/IBI (IBI-JBD) were tested for their ability to mitigate the effect of htt171-82Q. The overexpression of MEKK1(D1369A) and JIP-1/IBI reduced the polyQ-related loss of DARPP-32 expression, while the other inhibitors had no effect. In all cases, the formation of EM48-positive htt inclusions and P-c-Jun immunoreactivity were unaltered. These results suggest that JNK activation is involved in HD and that blockade of this pathway may be of benefit in counteracting HD-related neurotoxicity.
Mots-clé
Analysis of Variance, Animals, CREB-Binding Protein/metabolism, Cell Line, Transformed, Disease Models, Animal, Dopamine/metabolism, Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism, Female, Gene Expression Regulation/physiology, Humans, Huntington Disease/enzymology, Huntington Disease/genetics, Lentivirus/physiology, MAP Kinase Kinase 4/metabolism, Mutation/physiology, Nerve Tissue Proteins/genetics, Nerve Tissue Proteins/metabolism, Nuclear Proteins/genetics, Nuclear Proteins/metabolism, Proto-Oncogene Proteins c-jun/metabolism, Rats, Rats, Wistar, Serine/metabolism, Signal Transduction/physiology, Time Factors, Transfection/methods
Pubmed
Web of science
Création de la notice
13/12/2011 17:16
Dernière modification de la notice
20/08/2019 16:10
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