Molecular Insights into Parkinson's Disease Progression: A Multi-omics Analysis of the Substantia Nigra Pars Compacta across Braak Stages.

This integrated multi-omics study delineates molecular alterations in the substantia nigra pars compacta (SNpC) across different stages of Parkinson's disease (PD) in a Korean cohort. By combining transcriptomic and proteomic analyses of postmortem tissues, we identified stage-specific molecular signatures associated with Braak Lewy body pathology. Enrichment analyses revealed upregulation of extracellular matrix-related and immune response pathways, along with downregulation of genes involved in microtubule organization and neuronal function in the SNpC of PD patients. In addition, fifteen genes and fourteen proteins showing significant fold changes (>2.0 or <0.5), high normalized expression levels (log2 >3.0) and statistical significance (p<0.05) were profiled. Hierarchical clustering and principal component analysis of transcriptomic and proteomic data from SNpC tissues of PD patients (selected based on correlation coefficients >0.8 or <-0.8) revealed distinct stage-dependent groupings aligned with Braak Lewy body pathology. Molecular profiles correlated strongly with disease progression; advanced Braak stages exhibited disrupted mitochondrial processes and elevated phospholipid binding pathways, potentially linked to α-synuclein aggregation and neurodegeneration. Notably, upregulation of genes such as PARP3, SERPINE1, COQ10A, HMGB3 and LINC01094 was associated with α-synuclein aggregation, cell death, and autophagy inhibition, while downregulation of TXNIP, KIF25, and FTH1 co-occurred with neuronal loss and mitochondrial dysfunction. Proteomic analyses further highlighted increased levels of neuroinflammation and mitochondrial impairment markers, including SNCA, GPNMB, and LGALS3, some of which may serve as biomarkers of disease severity. These findings offer critical insights into PD's molecular pathogenesis and identify potential candidates for further functional validation and therapeutic intervention.