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Unravelling cell type specific response to Parkinson’s Disease at single cell resolution

ABSTRACT: Parkinson’s Disease (PD) is the second most common neurodegenerative disorder. The pathological hallmark of PD is loss of dopaminergic neurons and the presence of aggregated α-synuclein, primarily in the substantia nigra pars compacta (SNpc) of the midbrain. However, the molecular mechanisms that underlie the pathology in different cell types is not currently understood. Here, we present a single nuclei transcriptomic analysis of human post-mortem in substantia nigra pars compacta (SNpc) tissue from 15 sporadic Parkinson’s Disease (PD) cases and 14 Controls. Our dataset comprised of ∼80K nuclei, representing all major cell types of the brain and allowed us to obtain a transcriptome-level characterization of these cell types. Importantly, we identified multiple subpopulations for each cell type and described subpopulation-specific gene sets that provide insights into the differing roles of these subpopulations. Our findings revealed a significant decrease in neuronal cells in PD samples, accompanied by an increase in glial cells and T cells. Subpopulation analyses demonstrated a significant depletion of tyrosine hydroxylase (TH)-positive astrocyte, microglia, and oligodendrocyte populations, along with the TH-expressing neurons in PD samples, which were also depleted. Moreover, marker gene analysis of the depleted subpopulations identified 28 overlapping genes including those associated with dopamine metabolism (e.g., ALDH1A1, SLC6A3 & SLC18A2). Overall, our study provides a valuable resource for understanding the molecular mechanisms involved in dopaminergic neuron degeneration and glial responses in PD, highlighting the existence of novel subpopulations and cell type-specific gene sets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243639 | GEO | 2024/01/22

REPOSITORIES: GEO

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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.

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Unravelling cell type specific response to Parkinson’s Disease at single cell resolution

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