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Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy
Karine Merienne1, James Friedman, Masayuki Akimoto
1Department of Molecular Pathology, Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP10142, 67404 Illkirch Cédex, CU de Strasbourg, France. merienne@igbmc.u-strasbg.fr
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.
Insights
Cellular stress from polyglutamine expansion (polyQ) impairs vision in Spinocerebellar ataxia type 7 (SCA7). Compromising the JNK/c-Jun pathway improves Nrl gene expression and vision in a mouse model.
Area of Science:
- Neuroscience
- Genetics
- Cellular Biology
Background:
- Spinocerebellar ataxia type 7 (SCA7) involves polyglutamine expansion (polyQ) and retinal degeneration.
- PolyQ-ataxin-7 overexpression in rod photoreceptors activates the JNK/c-Jun stress pathway, causing dysfunction.
- SCA7 retinopathy is linked to reduced expression of rod-specific genes like Nrl.
Purpose of the Study:
- To investigate the role of cellular stress, specifically the JNK/c-Jun pathway, in SCA7 retinopathy.
- To determine if inhibiting JNK-mediated c-Jun activation can ameliorate SCA7-related vision loss.
- To elucidate the mechanism by which c-Jun affects Nrl gene expression.
Main Methods:
- Utilized the R7E mouse model with polyQ-ataxin-7 overexpression in rod photoreceptors.
- Bred R7E mice with JunAA knock-in mice, which have compromised JNK-mediated c-Jun activation.
- Analyzed gene expression of Nrl and its downstream targets involved in phototransduction.
Main Results:
- Breeding R7E mice with JunAA mice improved retinopathy.
- Expression of Nrl and phototransduction genes was partially restored in JunAA-R7E mice.
- Demonstrated that c-Jun directly represses Nrl transcription.
Conclusions:
- Polyglutamine-induced cellular stress contributes to the repression of essential neuronal genes.
- Inhibiting the JNK/c-Jun pathway offers a potential therapeutic strategy for SCA7 retinopathy.
- c-Jun acts as a direct repressor of Nrl, impacting rod photoreceptor function.