Dataset Information

Mass spectrometry-based proteomics analysis of human substantia nigra from Parkinson's disease patients identifies multiple pathways potentially involved in the disease

ABSTRACT: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) of the brain. Despite decades of studies, the precise pathogenic mechanism of PD is still elusive. An unbiased proteomic analysis of PD patients’ brains allows the identification of critical proteins and molecular pathways that lead to dopamine cell death and α-synuclein deposition and the resulting devastating clinical symptoms. In this study, we conducted an in-depth proteome analysis of human SN tissues from 15 PD patients and 15 healthy control (HC) individuals combining Orbitrap mass spectrometry with the isobaric tandem mass tag (TMT)-based multiplexing technology. We identified 10,040 proteins with 1,140 differentially expressed proteins in the SN of PD patients. Pathway analysis showed that the ribosome pathway was the most enriched one, followed by GABAergic synapse, retrograde endocannabinoid signaling, cell adhesion molecules (CAMs), morphine addiction, Prion disease, and Parkinson's disease pathways. Strikingly, the majority of the proteins enriched in the ribosome pathway were mitochondrial ribosomal proteins (mitoribosomes; MRPs). The subsequent protein-protein interaction (PPI) analysis and the weighted gene co-expression network analysis (WGCNA) confirmed that the mitoribosome is the most enriched protein cluster. Furthermore, the mitoribosome was also identified in our analysis of a replication set of 10 PD and 9 HC SN tissues. This study provides potential disease pathways involved in PD and paves the way to study further the pathogenic mechanism of PD.

INSTRUMENT(S): Orbitrap Fusion Lumos, LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Parkinson's Disease

SUBMITTER: chanhyun na

LAB HEAD: Chan Hyun Na

PROVIDER: PXD037684 | Pride | 2022-12-08

REPOSITORIES: Pride

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			Action	DRS
	PD_SN_Discovery_Set1_F01.raw	Raw
	PD_SN_Discovery_Set1_F02.raw	Raw
	PD_SN_Discovery_Set1_F03.raw	Raw
	PD_SN_Discovery_Set1_F04.raw	Raw
	PD_SN_Discovery_Set1_F05.raw	Raw

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Mass Spectrometry-Based Proteomics Analysis of Human Substantia Nigra From Parkinson's Disease Patients Identifies Multiple Pathways Potentially Involved in the Disease.

Jang Yura Y Pletnikova Olga O Troncoso Juan C JC Pantelyat Alexander Y AY Dawson Ted M TM Rosenthal Liana S LS Na Chan Hyun CH

Molecular & cellular proteomics : MCP 20221122 1

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) of the brain. Despite decades of studies, the precise pathogenic mechanism of PD is still elusive. An unbiased proteomic analysis of PD patient's brain allows the identification of critical proteins and molecular pathways that lead to dopamine cell death and α-synuclein deposition and the resulting devastating clinical symptoms. In this s ...[more]

PMID: 36423813

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Project description:Progressive supranuclear palsy (PSP) is a neurodegenerative disorder clinically characterized by progressive postural instability, supranuclear gaze palsy, parkinsonism, and cognitive decline caused by degeneration in specific areas of the brain including globus pallidus (GP), substantia nigra, and subthalamic nucleus. However, the pathogenetic mechanism of PSP remains unclear to date. Unbiased global proteome analysis of patients’ brain samples is an important step toward understanding PSP pathogenesis, as proteins serve as workhorses and building blocks of the cell. In this study, we conducted unbiased mass spectrometry-based global proteome analysis of GP samples from 15 PSP patients, 15 Parkinson disease (PD) patients, and 15 healthy control (HC) individuals. To analyze 45 samples, we conducted 5 batches of 11-plex isobaric tandem mass tag (TMT)-based multiplexing experiments, identifying 10,231 proteins. The gene set enrichment analysis results showed that the PD pathway was the most highly enriched, followed by pathways for oxidative phosphorylation, Alzheimer disease, Huntington disease, and non-alcoholic fatty liver disease (NAFLD) when PSP was compared to HC or PD. Most of the proteins enriched in the gene set enrichment analysis were mitochondrial proteins such as cytochrome c oxidase, NADH dehydrogenase, acyl carrier protein, succinate dehydrogenase, ADP/ATP translocase, cytochrome b-c1 complex, and/or ATP synthase. Strikingly, all of the enriched mitochondrial proteins in the PD pathway were downregulated in PSP compared to both HC and PD. The subsequent Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) protein-protein interaction (PPI) analysis and the weighted gene co-expression network analysis (WGCNA) further supported that the mitochondrial proteins were the most highly enriched in PSP. This is the first global proteome analysis of human GP from PSP patients, and this study paves the way to understanding the pathogenesis mechanism of PSP.