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Disease-modifying strategies for Parkinson disease (PD), the most common synucleinopathy, represent a critical unmet medical need. Accumulation of the neuronal protein alpha-synuclein (αS) and abnormal lipid metabolism have each been implicated in PD pathogenesis. We find that retinoid-X-receptor (RXR) nuclear receptor signaling can be leveraged to influence both these aspects of PD etiology. We find that activated RXR differentially regulates fatty acid desaturases, downregulating SCD5, the SCD isoform preferentially expressed in human brains. Reduction of SCD5 correlates with altered lipid droplet (LD) features such as reduced perilipin-2 levels, decreased LD size, and a reduction of triglyceride levels. With regard to αS proteostasis, our study reveals that RXR agonism stimulates lysosomal clearance of αS thereby reducing the cellular αS burden and improving cell health. Compared to RXR activation, use of an RXR antagonist had the opposite effects on LD size, SCD, αS turnover, and cytotoxicity supporting pathway specificity. Our work offers insight into a previously unrecognized connection between activated RXR, SCD5, and LDs and shows for the first time that activated RXR can modulate αS proteostasis. These multifaceted results implicate RXR-activating ligands in ameliorating phenotypes (lipid metabolism and αS) relevant to PD and offer a new paradigm to explore nuclear receptor ligands as a promising strategy for the treatment of PD/DLB and related synucleinopathies.
