Network Analysis and Human Single Cell Brain Transcriptomics Reveal Novel Aspects of Alpha-Synuclein (SNCA) Biology

et al. 2021

Preprint

Self Cite

Understanding disease biology at a cellular level from disease specific tissues is imperative for effective drug development for complex neurodegenerative diseases. We profiled 87,086 nuclei from putamen tissue of healthy controls, Parkinson's Disease (PD), and Multiple System Atrophy (MSA) subjects to construct a comprehensive single cell atlas. Although both PD and MSA are manifestations of alpha-synuclein protein aggregation, we observed that both the diseases have distinct cell-type specific changes. We see a possible expansion and activation of microglia and astrocytes in PD compared to MSA and controls. Contrary to PD microglia, we found absence of upregulated unfolded protein response in MSA microglia compared to controls. Differentially expressed genes in major cell types are enriched for genes associated with PD-GWAS loci. We found altered expression of major neurodegeneration associated genes, SNCA, MAPT, LRRK2, and APP, at cell-type resolution. We also identified disease associated gene modules using a network biology approach. Overall, this study creates an interactive atlas from synucleinopathies and provides major cell-type specific disease insights.

Section: Disease Specific Changes In Pd and Msa Neuronsmentioning

confidence: 77%

Single Cell Atlas of Human Putamen Reveals Disease Specific Changes in Synucleinopathies: Parkinson’s Disease and Multiple System Atrophy

Pande

Huang

et al. 2021

Preprint

Self Cite

“…Oligodendrocyte lineage nuclei were then subset from the integrated objects, to undergo reclustering and profiling to identify cell subtypes, evaluate their relationships by pseudotime trajectory analysis, and identify differentially expressed genes between disease (PD or MSA) and Control nuclei. Among oligodendrocyte lineage nuclei, oligodendrocyte precursor cells (OPC; markers: PDGFRA/VCAN), committed oligodendrocyte precursor cells (COP), and multiple clusters of oligodendrocytes (MOG/MAG/OPALIN/HAPLN2) have been described in previous studies [4,15]. Re-clustering of the OPC/Oligodendrocyte lineage cells was performed based on the rationale that unsupervised clustering of broad cell types might generate different cluster separations among oligodendrocyte subtypes than might be identified through applying the procedure only to oligodendrocyte lineage cells.…”

Section: Putamen Oligodendrocyte Populations Exhibit Molecular Diversitymentioning

confidence: 92%

“…In contrast, MSA occurs at a much lower frequency than PD, with an estimated mean incidence rate of 0.6-3 per 100,000 people [2,3]. In both PD and MSA, intracytoplasmic inclusions of α-synuclein are observed on post-mortem histologic examination, although the predominant cellular localization of α-synuclein differs between the two conditions: α-synuclein aggregates are observed mainly as neuronal intracellular aggregates (Lewy bodies) in PD [4,5] while in MSA, these aggregates occur most frequently as oligodendroglial cytoplasmic inclusions [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…Recent genome-wide association studies (GWAS) including large PD patient cohorts and new results from single-nucleus transcriptomic profiling in midbrain samples have highlighted potential roles for glial cells in the synucleinopathies, with particularly strong evidence implicating oligodendrocytes in PD [3][4][5][6][7]. Oligodendrocyte lineage cells have been proposed to participate in synucleinopathy development and progression via multiple mechanisms including insufficient metabolic support, initiation and propagation of exaggerated stress and inflammatory response signaling, and altered autophagy functions [3][4][5][6]. In a recently published single-nucleus RNA-seq analysis of substantia nigra tissue from healthy donors, oligodendrocytespecific differentially expressed genes were found to be associated with genes linked with variants significantly associated with PD by GWAS [3].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Single Nuclei Sequencing of Human Putamen Oligodendrocytes Reveals Altered Heterogeneity and Disease-Associated Changes in Parkinson’s Disease and Multiple System Atrophy

Joshi

et al. 2021

Preprint

Self Cite

The role of oligodendrocytes in neurodegenerative diseases remains incompletely understood and largely unexplored at the single cell level. We profiled 87,086 single nuclei from human brain putamen region for healthy control, Parkinsons Disease (PD), and Multiple System Atrophy (MSA). Oligodendrocyte lineage cells were the dominant cell-type in the putamen with oligodendrocyte subpopulations clustered by transcriptomic variation found to exhibit diverse functional enrichment patterns, and this oligodendrocyte heterogeneity was altered in a disease-specific way. Among profiled oligodendrocyte subpopulations, differences in expression of SNCA, HAPLN2, MAPT, APP, and OPALIN were observed for PD and MSA compared with healthy controls. Intriguingly, greater activation of unfolded protein response pathway gene expression was observed in PD nuclei versus MSA. Using network analysis, we then identified specific PD- and MSA-correlated gene co-expression modules enriched with disease relevant pathways; the PD-correlated module was significantly enriched for Parkinsons Disease GWAS loci (p = 0.01046). Our analysis provides a broader understanding of oligodendrocyte heterogeneity and reveals distinctive oligodendrocyte pathological alterations associated with PD and MSA which may suggest potential novel therapeutic targets and new strategies for disease modification.

“…al. [42]. Module genes were input to the NetworkAnalyst tool using the STRING interactome database [43] with confidence score cutoff 900. which filters differential interactions by percentile from the DifferentialNet database [11].…”

Section: Protein-protein Interaction Network Generationmentioning

confidence: 99%

Lysosomal-Immune Axis Is Associated with COVID 19 Disease Severity: Insights from Patient Single Cell Data

Pande

Huang

et al. 2021

Preprint

Self Cite

SARS-COV-2 has become a leading cause of illness, hospitalizations, and deaths worldwide yet heterogeneity in disease morbidity remains a conundrum. In this study, we analyzed publicly available single-cell RNA-seq data from 75076 cells sequenced from clinically staged COVID-19 patients using a network approach and identified lysosomal-immune axis as a factor significantly associated with disease severity. Our results suggest modulation of lysosomal-immune pathways may present a novel drug-targeting strategy to attenuate SARS-Cov-2 infections.