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

• Main Authors: Karine Merienne, James Friedman, Masayuki Akimoto, Gretta Abou-Sleymane, Chantal Weber, Anand Swaroop, Yvon Trottier
• Format: Article
• Language: English
• Published: Elsevier 2007-03-01
• Series: Neurobiology of Disease
• Subjects: Polyglutamine expansion; Neuronal stress; JNK/c-Jun pathway; Retina; Nrl; Photoreceptor
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996106002920

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 Nrl 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.