RNA-seq analysis of C. elegans sir-2.3 mutants vs wildtype
Huntington's disease is a rare neurodegenerative condition characterized by proteostasis imbalance and neuronal toxicity, with yet no cure. Here, we identify the mitochondrial sirtuin SIR-2.3/SIRT4 as a crucial modulator of polyglutamine (polyQ) and mutant huntingtin (mHtt) toxicity in C. elegans and in vitro mammalian models. Loss of sir-2.3 function results in neuronal rescue, which is AMPK- and autophagy-dependent. Transcriptomic analysis confirmed the upregulation of autophagy-related genes in sir-2.3 mutants. Notably, the protective effects of sir-2.3 ablation were partly dependent on DAF-16/FOXO and NHR-49/PPARa, which are known AMPK efefctors and regulate genes involved in autophagy and metabolism. We also use soft ATP synthetase inhibitors, to emulate the effect of ablating sir-2.3, to reduce neuronal toxicity induced by mHtt. These findings establish the SIRT4-AMPK as a key regulator linking mitochondrial metabolism, autophagy, and neuronal resilience, providing for more druggable targets to restore proteostasis in HD and, may be, in other neurodegenerative diseases that involve protein imbalance.