Molecular Insights into Parkinson’s Disease Progression: A Multi-omics Analysis of the Substantia Nigra Pars Compacta across Braak Stages
6 affiliations
- 1Mthera Pharma Co., Ltd. Seoul 07793 Korea
- 2Department of Biology, Hood College, Frederick MD 21701 USA
- 3Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505 Daegu 41062 Korea
- 4Department of Neurology, Busan Paik Hospital, Inje University College of Medicine, Busan 47392 Daegu 41062 Korea
- 5Department of Neurology, Kangwon National University School of Medicine, Chuncheon 24289 Daegu 41062 Korea
- 6Korea Brain Bank, Korea Brain Research Institute Daegu 41062 Korea
Abstract
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.
Related
- Temporal interference stimulation rescues dopaminergic neurons in the substantia nigra of MPTP-induced Parkinson’s disease mice via inhibition of lipid peroxidation
- Carotid atherosclerosis progression in patients with Parkinson’s disease: a prospective cohort study
- A novel eye-tracking oculomotor score correlates with excessive daytime sleepiness and motor progression in Parkinson’s disease
- Association of GBA1 status and sex with depression severity and progression in Parkinson’s disease
- Progression GWAS followed by functional characterization implicates E3 ubiquitin ligase TRIM2 as a potential genetic modifier of Parkinson’s disease progression
BibTeX
@article{kim2026molecular,
title = {{Molecular Insights into Parkinson’s Disease Progression: A Multi-omics Analysis of the Substantia Nigra Pars Compacta across Braak Stages}},
author = {Sinyeon Kim and Jin Gyu Choi and Se Woong Kim and Miwon Son and Daehwan Kim and Soo Jeong Nam and Sang Jin Kim and Seongheon Kim and Korea Brain Bank Network},
journal = {Experimental Neurobiology},
year = {2026},
month = oct,
doi = {10.5607/en25051},
url = {https://doi.org/10.5607/en25051},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Molecular Insights into Parkinson’s Disease Progression: A Multi-omics Analysis of the Substantia Nigra Pars Compacta across Braak Stages
AU - Sinyeon Kim
AU - Jin Gyu Choi
AU - Se Woong Kim
AU - Miwon Son
AU - Daehwan Kim
AU - Soo Jeong Nam
AU - Sang Jin Kim
AU - Seongheon Kim
AU - Korea Brain Bank Network
PY - 2026
DA - 2026/10/31
JO - Experimental Neurobiology
DO - 10.5607/en25051
UR - https://doi.org/10.5607/en25051
AB - 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.
SN - 1226-2560
SN - 2093-8144
ER -