Single-cell transcriptomic and proteomic analysis of Parkinson’s disease Brains

Abstract

Parkinson's disease (PD) is a prevalent neurodegenerative disorder where recent evidence suggests pathogenesis may be mediated by inflammatory processes. The molecular architecture of the disease remains to be fully elucidated. We performed single-nucleus transcriptomics and unbiased proteomics using postmortem tissue obtained from the prefrontal cortex of 12 individuals with late-stage PD and age-matched controls. We analyzed ~80,000 nuclei and identified eight major cell types, including brain-resident T cells, each with distinct transcriptional changes in line with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem tissue, we found that a-synuclein pathology is inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in prefrontal cortex that were preferentially downregulated in PD. Strikingly, comparing this dataset to a regionally similar published analysis for Alzheimer's disease (AD), we found no common differentially expressed genes in neurons, but identified many shared differentially expressed genes in glial cells, suggesting that disease etiology in PD and AD are likely distinct. These data are presented as a resource for interrogating the molecular and cellular basis of PD and other neurodegenerative diseases.

A Markov random field model-based approach for differentially expressed gene detection from single-cell RNA-seq data

“…For example, metallothioneins 1G (MT1G) was found in PD frontal cortex and expressed by astrocytes to protect neurons [ 63 , 64 ]. Also, heat shock response genes HSPA1A were downregulated in PD patients neurons [ 18 , 65 ], and our results suggest that they are also DE genes in OPCs and oligodentrocytes, but upregulated. Morevoer, dual specificity phosphatase 1 (DUSP1) was shown to be upregulated in PD to overcome neuron damage [ 66 , 67 ].…”

“…Finally, we applied our model to a single cell dataset containing post-mortem human brain tissue from the prefrontal cortex of six PD patients (denoted by PD142, PD148, PD151, PD197, PD199 and PD208) and six healthy controls (HC) (denoted by HC07, HC10, HC101, HC13, HC30 and HC99) in a recent study [ 18 ]. We filtered out T cells and endothelial cells which only made up 1.13% of the total population (Figure 4 A and B, Supplementary Figure 9A , see Supplementary Data available online at http://bib.oxfordjournals.org/ ), resulting in 15 891 genes and 76 212 cells.…”

A topographical atlas of αSyn dosage and cell-type expression in the mouse brain and periphery

“…Some populations of Olig2+ cells, however, expressed a considerable amount of aSyn. These are likely oligodendrocyte precursor cells (OPCs) which have previously been reported to express a relatively high level of aSyn 60,33,[61][62][63][64] . The role that aSyn plays within these cells remains enigmatic, but higher native expression in OPCs, in concert with genetic and/or environmental insults, may predispose a cell to future pathology in diseases like MSA, where aSyn pathology principally occurs in oligodendrocytes.…”

Mitochondrial dysfunction is a key pathological driver of early stage Parkinson’s

“…Analysis of the cell type-specific protein expression was performed in a number of available datasets: mouse brain proteomics generated by Sharma et al [34], human brain transcriptomics and proteomics [35,36] and mouse PD transcriptomics [37] to assess for enrichment of the significantly associated proteins/genes in particular brain cell types. Enrichment analysis was performed using Bioconductor R package GeneOverlap [38] that returns the Fisher's exact test p-value and odds ratio as previously performed in Wingo et al, [39].…”