Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

NEUROBIOLOGY OF DISEASE

卷:25

Article

Merienne, Karine ; Friedman, James ; Akimoto, Masayuki ; Abou-Sleymane, Gretta ; Weber, Chantal ; Swaroop, Anand ; Trottier, Yvon

关键词: polyglutamine expansion;    neuronal stress;    JNK/c-Jun pathway;    retina;    Nrl;    photoreceptor;    gene regulation;   

DOI  :  10.1016/j.nbd.2006.11.002

来源: Elsevier

【 摘 要 】

We have approached the role of cellular stress in neurodegenerative diseases caused by polyglutamine expansion (polyQ) in the context of Spinocerebellar ataxia type 7 (SCA7) that includes retinal degeneration. Using the R7E mouse, in which polyQ-ataxin-7 is specifically over-expressed in rod photoreceptors, we previously showed that rod dysfunction correlated to moderate and prolonged activation of the JNK/c-Jun stress pathway. SCA7 retinopathy was also associated with reduced expression of rod-specific genes, including the transcription factor Nrl, which is essential for rod differentiation and function. Here, we report that R7E retinopathy is improved upon breeding with the JunAA knock-in mice, in which JNK-mediated activation of c-Jun is compromised. Expression of NO and its downstream targets, which are involved in phototranduction, are partially restored in the JunAA-R7E mice. We further show that c-Jun can directly repress the transcription of Nrl. Our studies suggest that polyQ-induced cellular stress leads to repression of genes necessary for neuronal fate and function. (c) 2006 Elsevier Inc. All rights reserved.

【 授权许可】

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