Rhes as a Potential Modulator of PINK1/Parkin-Dependent Mitophagy in Huntington’s Disease

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin (HTT) gene, resulting in progressive motor, cognitive, and psychiatric impairment. Despite the widespread expression of mutant huntingtin (mHTT), disease progression is characterized by the selective degeneration of striatal neurons. Mitochondrial dysfunction and impaired mitophagy have emerged as important contributors to HD pathogenesis; however, the mechanisms underlying defective mitochondrial quality control remain incompletely understood. Ras homolog enriched in the striatum (Rhes), a small striatal-enriched guanosine triphosphatase (GTPase), has been implicated in mitophagy-related signalling. In this study, we examined the potential relationship between Rhes and PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy in HD. We propose that Rhes contributes to selective striatal vulnerability by promoting mitochondrial depolarization through BCL2 interacting protein 3-like (NIX/BNIP3L), facilitating activation of the PINK1/Parkin mitophagy pathway, while enhancing autophagosome biogenesis through Beclin-1 signalling. If validated, our proposed pathway would open new avenues for therapeutic development in HD.