Dataset Information

Proteomic Profiling of the Substantia Nigra to Identify Determinants of Lewy Body Pathology and Dopaminergic Neuronal Loss

ABSTRACT: Proteinaceous aggregates containing alpha-synuclein protein called Lewy bodies in the substantia nigra is a hallmark of Parkinson's disease. The molecular mechanisms of Lewy body formation and associated neuronal loss remain largely unknown. To gain insights on proteins and pathways associated with Lewy body pathology, we performed quantitative profiling of the proteome. We analyzed substantia nigra tissue from 51 subjects arranged into three groups: cases with Lewy body pathology, Lewy body-negative controls with matching neuronal loss and controls with no neuronal loss. Using label-free LC-MS/MS approach we quantified the 2,963 most abundant proteins. Statistical testing for differential protein abundance, followed by pathway enrichment and Bayesian learning of the causal network structure were performed to identify likely drivers of Lewy body formation and dopaminergic neuronal loss. The identified pathways include (1) Arp2/3 complex-mediated actin nucleation; (2) synaptic function; (3) poly(A) RNA binding; (4) basement membrane and endothelium; and (5) hydrogen peroxide metabolic process. According to the data, the endothelial/basement membrane pathway is tightly connected with both pathologies and likely to be one of the drivers of the neuronal loss. The poly(A) RNA-binding proteins, including the ones relevant to other neurodegenerative disorders (e.g. TDP-43 and FUS) have strong inverse correlation with Lewy bodies and may reflect alternative mechanism of nigral neurodegeneration.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Substantia Nigra

DISEASE(S): Parkinson's Disease

SUBMITTER: Matthew Monroe

LAB HEAD: Vladislav A Petyuk

PROVIDER: PXD019279 | Pride | 2022-08-11

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	H_sapiens_Uniprot_SPROT_2015-04-22.fasta	Fasta
	Lewy2_10Cs_2Nov13_Samwise_13-07-28.raw	Raw
	Lewy2_10Ct1_2Nov13_Samwise_13-07-28.raw	Raw
	Lewy2_10Ct2_2Nov13_Samwise_13-07-28.raw	Raw
	Lewy2_11Cs_2Nov13_Samwise_13-07-28.raw	Raw

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Publications

Proteomic Profiling of the Substantia Nigra to Identify Determinants of Lewy Body Pathology and Dopaminergic Neuronal Loss.

Petyuk Vladislav A VA Yu Lei L Olson Heather M HM Yu Fengchao F Clair Geremy G Qian Wei-Jun WJ Shulman Joshua M JM Bennett David A DA

Journal of proteome research 20210426 5

Proteinaceous aggregates containing α-synuclein protein called Lewy bodies in the substantia nigra is a hallmark of Parkinson's disease. The molecular mechanisms of Lewy body formation and associated neuronal loss remain largely unknown. To gain insights into proteins and pathways associated with Lewy body pathology, we performed quantitative profiling of the proteome. We analyzed substantia nigra tissue from 51 subjects arranged into three groups: cases with Lewy body pathology, Lewy body-negat ...[more]

PMID: 33900085

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Project description:Progression through neuronal loss of substantia nigra pars compacta with Parkinson’s disease depends on various protein post-translational modifications mainly comprising phosphorylation, ubiquitination, acetylation, and methylation. Phosphorylation and ubiquitination regulate major physiological changes and cellular signaling pathways during dopaminergic neuronal death. Phosphorylation and ubiquitination dyshomeostasis of substantia nigra pars compacta tissue occurs earlier than movement symptom appearance. Although many phosphorylation and ubiquitination sites have been identified through site-specific methods, systematic quantitative proteomic analysis of pre-symptomatic Parkinson’s disease remains unexplored. Using quantitative proteomics, we have globally profiled ubiquitination and phosphorylation in substantia nigra pars compacta tissue of a Parkinson’s disease transgenic mouse model (A30P*A53T α-synuclein, hm2α-SYN-39 mouse strain) at pre-symptomatic stage; Our datasets of 5,351 phosphorylation sites in 2,136 proteins and 3,971 ubiquitination sites in 1,595 proteins provide valuable insight into pre-symptomatic Parkinson’s disease. After in-depth analysis of the relationship between phosphorylation and ubiquitination sites, we concluded that correlation of the relationship increased with decreasing distance. Subsequent bioinformatic analyses, including gene ontology annotation, domain annotation, subcellular localization, KEGG pathway annotation, functional cluster analysis, and motif analysis were performed to annotate quantifiable targets of phosphorylation and ubiquitination sites. Individual simultaneous phosphorylation and ubiquitination proteins that were differentially quantified were screened. The endocytosis pathway is likely regulated by both phosphorylation and ubiquitination at the molecular protein Epn2 (S439 and K135) in early-stage Parkinson’s disease. Therefore, this elucidation of the dysregulation of phosphorylation and ubiquitination has implications for understanding the pathophysiological mechanism of dopaminergic neuron degeneration and for developing novel therapeutics for Parkinson’s disease.