I027 The mitochondrial sirtuin sir-2.3/SIRT4 modulates neuronal function in C. elegans models of Huntington disease

<h3>Background</h3> Huntington disease (HD) is a hereditary neurodegenerative disorder characterized by an expanded CAG repeat in the HTT gene, resulting in abnormal huntingtin protein. This mutant protein (mHtt) forms insoluble aggregates, leading to neurodegeneration primarily in the cortex and striatum. While there’s an inverse correlation between CAG repeat length and age of onset, variability in disease onset suggests the influence of genetic and environmental modifiers. Identifying these modifiers could unveil therapeutic targets. <h3>Aims</h3> This study explores the role of mitochondrial sirtuins sir-2.3/SIRT4, and its downstream effectors, in modulating neuronal protein aggregation and behavioural phenotypes in Caenorhabditis elegans models of polyglutamine-associated diseases and HD. <h3>Methods</h3> We used C. elegans models expressing polyQs in neuronal tissue to study the effects of sir-2.3 and sir-2.2 loss of function. PolyQ aggregation was analysed using fluorescence microscopy, motor function was assessed with thrashing assays, and neuronal function was examined through touch response assays. Downstream targets were investigated using genetic mutants. <h3>Results</h3> Our results show that sir-2.3 depletion reduces neuronal polyQ aggregation, enhances motility, and improves touch response in an AMPK-dependent manner, likely via autophagy activation. sir-2.2 appears to negatively regulate sir-2.3. Loss of sir-2.2 exacerbates polyQ toxicity, likely due to uninhibited sir-2.3 activity. However, simultaneous deletion of sir-2.2 and sir-2.3 yields a phenotype similar to sir-2.3 deletion. <h3>Conclusions</h3> Loss of sir-2.3/SIRT4 reduces neuronal polyQ aggregation and rescues motor and neuronal function in C. elegans, presumably mediated by AMPK and autophagy activation. These results suggest that targeting sir-2.3/SIRT4-dependent signalling pathways could be a potential therapeutic strategy for HD.