Integrative Transcriptomic Meta-Analysis Reveals SIRT1-SNCA Correlation in Parkinson's Disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects midbrain dopaminergic neurons without any approved therapy. Candidate molecular targets identified in one model are not always traceable across the postmortem, induced pluripotent stem cell (iPSC), and cell-based systems used to study PD, which complicates clinical translation. To address this gap, we performed an integrative transcriptomic meta-analysis of 33 publicly available datasets across postmortem human brain, iPSC-derived models, and dopaminergic cell lines of PD. Differential expression and functional enrichment analyses were combined with STRING protein-protein interaction networks, followed by drug-gene interaction screening against a polyphenol panel. Overall, resveratrol was recovered in all 33 comparisons, independent of model system, tissue, and genetic background. We associated resveratrol with 30 distinct target genes, and SIRT1 was itself a recovered target in 6 comparisons spanning all three model systems. Finally, we resolved the SIRT1-SNCA relationship into four directional patterns that differed by model, inverse in postmortem brain and positive in acutely toxin-exposed cells. These findings support a candidate, context-dependent resveratrol-SIRT1 axis in PD.