Perrin V, Dufour N, Raoul C, Hassig R, Brouillet E, Aebischer P, Luthi-Carter R, Déglon N
Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Exp Neurol. 2009 Jan;215(1):191-200. doi: 10.1016/j.expneurol.2008.10.008. Epub 2008 Oct 28.
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.
亨廷顿舞蹈病（HD）是一种神经退行性疾病，由亨廷顿蛋白（htt）N端谷氨酰胺重复序列（polyQ）的扩增所致。此前研究表明，含polyQ的蛋白表达可诱导多种细胞应激反应。其中，在HD细胞模型中观察到c-Jun N端激酶（JNK）级联反应被激活。然而，此前尚未在HD动物模型的纹状体中评估JNK通路的作用。在此，我们报告JNK通路参与了该疾病大鼠模型的HD病理过程。早在慢病毒介导的htt171-82Q表达4周后，就观察到JNK靶标c-Jun的磷酸化增加，并持续了13周。为了评估该通路在HD病理中的重要性，测试了包括上游激酶显性负突变体（ASK1(K709R)、MEKK1(D1369A)）、c-Jun突变体（Delta169c-Jun）以及支架蛋白JIP-1/IBI的活性结构域（IBI-JBD）在内的JNK抑制剂减轻htt171-82Q作用的能力。MEKK1(D1369A)和JIP-1/IBI的过表达减少了与polyQ相关的DARPP-32表达缺失，而其他抑制剂则无此作用。在所有情况下，EM48阳性htt包涵体的形成和P-c-Jun免疫反应性均未改变。这些结果表明JNK激活参与了HD，阻断该通路可能有助于对抗HD相关的神经毒性。
