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

Abstract

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.

Protection Against Chronic Hypoperfusion-Induced Retinal Neurodegeneration by PARP Inhibition via Activation of PI-3-kinase Akt Pathway and Suppression of JNK and p38 MAP Kinases

“…Retinal ischemia induced by elevation of intraocular pressure leads to activation of JNK and p38 MAP kinases within the first 6 h (Roth et al 2003;Merienne et al 2007;Roduit and Schorderet 2008). Long-term activation of MAP kinases has also been reported in excitotoxic retinal damage, with activation beginning 1-6 h after the NMDA treatment or the ischemic insult (Zhang et al 2002;Munemasa et al 2005).…”

“…Another group of rats underwent the same surgical procedure for bilateral carotid occlusion (n = 9) or sham operation (n = 5) and retinas were removed after 4 h in order to investigate the signaling pathways that are activated within the first few hours after an ischemic insult (Roth et al 2003;Merienne et al 2007;Roduit and Schorderet 2008). Samples were processed for Western blot analysis as described earlier (Racz et al 2007).…”

Mouse Models of SCA3 and Other Polyglutamine Repeat Ataxias

“…R7E transgenic mice develop a phenotype earlier than P7E mice, with a pathology that includes NIIs formation, retinal photoreceptor dysfunction, and neurodegeneration (Helmlinger et al, 2004aYefimova et al, 2010;Yvert et al, 2000). Notably, the deactivation of the JNK/c-Jun stress pathway in R7E mice ameliorates retinopathy and may be a promising finding for future therapies (Merienne et al, 2007). In the R7E mouse retina, mutant ataxin-7 alters the recruitment of the SAGA complex to chromatin resulting in H3 hyperacetylation, leading to transcriptional deregulation of rod differentiation and retinopathy .…”

“…Among other therapeutic strategies under investigation for polyQ ataxias are modulation of signal transduction pathways (Merienne et al, 2007), induction of neuroprotective effects with growth factors or stem cell transplantation (Chang et al, 2011a,b;Noma et al, 2012), and modulation of calpain activity (Simões et al, 2012).…”

Genetically engineered mouse models of the trinucleotide-repeat spinocerebellar ataxias

“…Expression-analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. When these mice were crossed with a knock-in line expressing JUNAA, an alanine-substituted form of jun which is inactive, the retinal phenotype was improved and there was restoration of Nrl, a factor active in transcription of rod-specific proteins [62]. …”