Olfactory proteomics reveals the capacity of the HDAC1 inhibitor pyroxamide to halt the α‐synuclein preformed fibrils‐induced damage in nasal epithelial, microglial and dopaminergic neuronal cell lines

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Parkinson's disease (PD) is the second most common neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons originating in the substantia nigra (SN) pars compacta and projecting to other brain regions, giving rise to motor and non-motor symptoms. Despite significant progress in understanding the molecular and cellular disruptions associated with PD, there remains an unmet clinical need for effective therapies. In this study, proteomic analysis of the olfactory tract (OT) in controls with no known neurological history (n = 17) and PD subjects (n = 21) revealed Lewy body disease (LBD) stage-dependent proteostatic impairment, accompanied by progressive modulation of the alpha-synuclein (α-syn) functional interactome. Differential OT omic profiles were used in a computational drug repurposing approach, revealing the HDAC1 inhibitor pyroxamide as one of the top drug candidates with in silico potential to restore altered OT omic profiles. To explore the potential therapeutic effects of pyroxamide, in vitro assays were performed using α-syn preformed fibrils (PFFs). Pyroxamide treatment reduced α-syn PFFs-induced toxicity in olfactory epithelial, microglial and dopaminergic neuronal cell lines, producing a protective effect against hydrogen peroxide-induced damage exclusively in brain-derived cell types. Mechanistically, the mitigating effects of pyroxamide were attributable, at least in part, to the regulation of Bax-1 and sirtuin 1 (SIRT1) protein expression, along with alterations in the mRNA levels of NEF2L2, IL1B, and TNF-α. These findings confirm the suitability of omics profiles in drug repurposing workflows against PD, offering valuable insights into the potential of HDAC1 inhibitors in the therapeutic pipeline of PD.

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