Perillaldehyde alleviates polyQ‐induced neurodegeneration through the induction of autophagy and mitochondrial UPR in Caenorhabditis elegans

Huntington's disease (HD) is a fatal neurodegenerative disease associated with autophagy disorder and mitochondrial dysfunction. Here, we identified therapeutic potential of perillaldehyde (PAE), a monoterpene compound obtained from Perilla frutescens (L.) Britt., in the Caenorhabditis elegans (C. elegans) model of HD, which included lifespan extension, healthspan improvement, decrease in polyglutamine (polyQ) aggregation, and preservation of mitochondrial network. Further analyses indicated that PAE was able to induce autophagy and mitochondrial unfolded protein reaction (UPR^mt) activation and positively regulated expression of associated genes. In lgg‐1 RNAi C. elegans or C. elegans with UPR^mt‐related genes knockdown, the effects of PAE treatment on polyQ aggregation or rescue polyQ‐induced toxicity were attenuated, suggesting that its neuroprotective activity depended on autophagy and UPR^mt. Moreover, we found that pharmacological and genetic activation of UPR^mt generally protected C. elegans from polyQ‐induced cytotoxicity. Finally, PAE promoted serotonin synthesis by upregulating expression of TPH‐1, and serotonin synthesis and neurosecretion were required for PAE‐mediated UPR^mt activation and its neuroprotective activity. In conclusion, PAE is a potential therapy for polyQ‐related diseases including HD, which is dependent on autophagy and cell‐non‐autonomous UPR^mt activation.