SSRI-1 Reduces Mutant Huntingtin Accumulation via SUMOylation Inhibition and Induction of Autophagic Flux

Huntington's disease (HD) is a rare neurodegenerative disorder caused by mutant huntingtin (mHtt), whose accumulation and aggregation drive progressive neuronal dysfunction and death. Currently there is no cure. SUMOylation has been implicated in mHtt aggregation, suggesting this pathway as a therapeutic target. We previously showed that SSRI-1 acts as a global SUMOylation inhibitor. Here, we investigated whether SSRI-1 reduces mHtt accumulation through modulation of SUMOylation. SUMO1/SUMO2 overexpression alone in HEK293T cells expressing HttQ74-mCherry increased mHtt aggregate formation (Western blot, WB). Both SSRI-1 and ML792, an irreversible SUMOylation inhibitor, decreased SUMOylation and mHtt aggregate formation (WB, immunofluorescence). Under saturating SUMO1/SUMO2 overexpression, this effect was lost, indicating dependence on limiting free SUMO availability. Nickel-agarose pull-down confirmed reduced mHtt SUMOylation after SSRI-1 or ML792 treatment. Both inhibitors also induced autophagic flux, suggesting an additional clearance mechanism. Consistently, SSRI-1 and ML792 decreased endogenous Htt in HD patient fibroblasts, an effect abolished by autophagy inhibition, confirming autophagy-mediated clearance. These findings identify SUMOylation as a druggable pathway regulating mHtt via aggregation and autophagy, supporting SSRI-1 repurposing as a disease-modifying strategy for HD.