Valosin-Containing Protein as a therapeutic target in CAG repeat-driven Spinocerebellar ataxias: Integrative transcriptomic and computational insights.

Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders caused by abnormal CAG repeat expansions in genes such as ATXN1, ATXN2, and ATXN3, with no effective therapeutic options currently available. To identify key molecular drivers of disease pathology, transcriptomic datasets GSE75249 and GSE151276 were analyzed. Differentially expressed genes were determined, and overlapping upregulated genes from both datasets were extracted for downstream analysis. Functional enrichment revealed significant biological processes and pathways related to protein homeostasis, cellular stress response, and neurodegeneration. Protein-protein interaction networks were constructed to investigate gene connectivity, and hub gene analysis identified Valosin-Containing Protein (VCP) as the top-ranked common hub gene. Importantly, VCP expression was experimentally validated in plasma samples from SCA1, SCA2, and SCA3 patients using ELISA, confirming its dysregulation and central role in SCA pathogenesis. To explore therapeutic potential, pharmacophore-based virtual screening of natural compounds was conducted, followed by molecular docking to evaluate interactions with VCP. Among the shortlisted candidates, sesamolin demonstrated the strongest binding affinity and favorable pharmacological properties. A 250 ns molecular dynamics simulation further confirmed the stability of the VCP-sesamolin complex, revealing sustained interactions, reduced fluctuations, and conformational stabilization of VCP. Collectively, this integrative approach combining transcriptomic profiling, enrichment analysis, hub gene identification, experimental validation, and structure-based drug discovery highlights VCP as a crucial regulator in CAG repeat-associated SCAs and proposes sesamolin as a promising neuroprotective lead compound for further preclinical development.