Vorinostat Rescues SQSTM1 Palmitoylation and Restores Dysfunctional Autophagy in Huntington Disease

Abstract Protein mislocalization, dysfunctional autophagy, and protein aggregation are key features of Huntington disease (HD). Accordingly, a central focus of our work has been identifying and correcting the protein mislocalization that drives the underlying autophagic defects which exacerbates protein aggregation. We previously demonstrated that palmitoylation, or S-acylation, of the autophagy receptor sequestosome 1 (SQSTM1; p62) is significantly reduced in the brains of HD patients and the YAC128 HD mouse model, thereby providing a possible mechanism for the cargo-loading failure observed in HD. Here, we identify the FDA-approved small molecule Vorinostat (suberoylanilide hydroxamic acid, SAHA) as a modulator of this pathway and show that it rescues SQSTM1 palmitoylation and restores autophagic function in HD models. Importantly, we demonstrate that Vorinostat crosses the blood-brain-barrier and significantly increases SQSTM1 palmitoylation in the cortices of YAC128 mice using acyl-biotin exchange and click chemistry assays. We further show that Vorinostat enhances autophagic flux, as evidenced by significant changes in autophagy marker levels and a marked increase in the colocalization of huntingtin with SQSTM1 and lysosomes. Finally, we investigate the mechanism of Vorinostat and propose a dual mode of action involving inhibition of depalmitoylating enzymes and transcriptional regulation of key pathway components. Collectively, these findings underscore SQSTM1 palmitoylation as a promising therapeutic target and support Vorinostat as a strong therapeutic candidate in HD.