Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/11640
Title: Implication of the JNK pathway in a rat model of Huntington's disease.
Authors: Perrin, V
Dufour, N
Raoul, C
Hassig, R
Brouillet, E
Aebischer, P
Luthi-Carter, R
Déglon, N
First Published: Jan-2009
Citation: EXP NEUROL, 2009, 215 (1), pp. 191-200
Abstract: 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.
DOI Link: 10.1016/j.expneurol.2008.10.008
eISSN: 1090-2430
Links: http://hdl.handle.net/2381/11640
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Cell Physiology and Pharmacology

Files in This Item:
There are no files associated with this item.


Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.