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Cell death mechanisms in a mouse model of retinal degeneration in Spinocerebellar ataxia 7

DOI:10.1016/j.neuroscience.2018.12.051 期刊:Neuroscience 出版年份:2019 更新时间:2025-09-23 15:22:29
摘要: Spino-cerebellar ataxia type 7 (SCA7) is a polyglutamine (polyQ) disorder characterized by neurodegeneration of the brain, cerebellum, and retina caused by a polyglutamine expansion in ataxin 7. The presence of an expanded polyQ tract in a mutant protein is known to induce protein aggregation, cellular stress, toxicity, and finally cell death. However, the consequences of the presence of mutant ataxin7 in the retina and the mechanisms underlying photoreceptor degeneration remain poorly understood. In this study, we show that in a retinal SCA7 mouse model, polyQ ataxin7 induces stress within the retina and activates Muller cells. Moreover, Unfolded Protein Response and autophagy are activated in SCA7 photoreceptors. We have also shown that the photoreceptor death does not involve a caspase-dependent apoptosis but instead involves apoptosis inducing factor (AIF) and Leukocyte Elastase Inhibitor (LEI/L-DNase II). When these two cell death effectors are downregulated by their siRNA, a significant reduction of photoreceptor death is observed. These results highlight the consequences of polyQ protein expression in the retina and the role of caspase-independent pathways involved in photoreceptor cell death.
作者: Cecile Lebon,Francine Behar-Cohen,Alicia Torriglia
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Investigating the mechanisms of photoreceptor cell death due to polyglutamine toxicity induced by expanded ataxin7 expression in a mouse model of Spinocerebellar ataxia 7.

The study demonstrates that photoreceptor cell death in SCA7 mice is caspase-independent and involves AIF and LEI/L-DNase II pathways. Downregulation of these effectors reduces cell death, highlighting their role. Calpain inhibition also reduced cell death, suggesting involvement in effector activation. The findings provide insights into polyQ toxicity mechanisms in the retina and suggest potential therapeutic targets for neurodegenerative disorders.

The study is limited to a specific mouse model (SCA7 R7E) and may not fully represent human SCA7 pathology. The low number of samples required non-parametric statistical tests, potentially reducing power. siRNA inhibition did not completely abolish cell death, suggesting other pathways may be involved or inefficiencies in knockdown. The cellular model (HEK293 cells) may not fully recapitulate retinal conditions. The mechanisms of autophagy and UPR activation were not fully elucidated.

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