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

Karine Merienne (1) , James S. Friedman (2) , Masayuki Akimoto (2) , Gretta Abou-Sleymane (1, 3) , Chantal Weber (1) , Anand Swaroop (2) , Yvon Trottier (1, 3)

1 IGBMC - Institut de génétique et biologie moléculaire et cellulaire
2 Department of Ophthalmology and Visual Sciences
3 Collège de France - Chaire Génétique Humaine

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.

Domaines: Biologie moléculaire

Karine Merienne, James S. Friedman, Masayuki Akimoto, Gretta Abou-Sleymane, Chantal Weber, et al.. Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy.. Neurobiology of Disease, 2007, 25 (3), pp.571-81. ⟨10.1016/j.nbd.2006.11.002⟩. ⟨hal-00190952⟩