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Rabu, M.

Publications and source records attributed to Rabu, M..

2 recordsLinked to original sources
bioRxiv2026

Brain and neuronal expression and localization of de-S-acylating enzymes

S-acylation is a reversible posttranslational lipid modification important in the nervous system that dynamically regulates protein localization and function. Aberrant S-acylation has been implicated in several neurological conditions. While several de-S-acylases (deacylases hereafter) have been identified, little is known regarding their expression and localization in the brain and in neurons. Here, we characterized the expression, localization, and S-acylation of cytosolic deacylases, including acyl-protein thioesterases APT1, APT2, and APT1L and /{beta} hydrolase domain-containing proteins ABHD7, ABHD10, ABHD13, ABHD16A, and ABHD17A-C. Mouse brain RNA sequencing data reveal high expression of Lypla1/APT1, Lypla2/APT2, Ephx4/ABHD7, Abhd16a, and Abhd17A-C in the brain, whereas Lyplal1/APT1L, Abhd10, and Abhd13 were expressed at very low levels. At the protein level, APT1 and ABHD16A levels are highest in the cerebellum with ABHD17A levels lowest in this region while APT2 levels are highest in the hippocampus. However, all four are abundant in cultured hippocampal neurons. Deacylases are localized throughout neurons on punctate structures, with APT2 and ABHD17C localized to the Golgi. Finally, all ten cytosolic deacylases are themselves S-acylated. These data characterizing deacylase expression, localization, and S-acylation in neural contexts, provides a foundation for future studies investigating deacylase neuronal functions and potential roles in neurological disease.

neuroscience↗
bioRxiv2026

Vorinostat Rescues SQSTM1 Palmitoylation and Restores Dysfunctional Autophagy in Huntington Disease

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.

neuroscience↗