Abstract
Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized with dopaminergic neuron (DaN) loss within the substantia nigra (SN). Despite bulk studies focusing on intracellular mechanisms of PD inside DaNs, few studies have explored the pathogeneses outside DaNs, or between DaNs and other cells. Here, we set out to probe the implication of intercellular communication involving DaNs in the pathogeneses of PD at a systemic level with bioinformatics methods. We harvested three online published single-cell/single-nucleus transcriptomic sequencing (sc/snRNA-seq) datasets of human SN (GSE126838, GSE140231, and GSE157783) from the Gene Expression Omnibus (GEO) database, and integrated them with one of the latest integration algorithms called Harmony. We then applied CellChat, the latest cell–cell communication analytic algorithm, to our integrated dataset. We first found that the overall communication quantity was decreased while the overall communication strength was enhanced in PD sample compared with control sample. We then focused on the intercellular communication where DaNs are involved, and found that the communications between DaNs and other cell types via certain signaling pathways were selectively altered in PD, including some growth factors, neurotrophic factors, chemokines, etc. pathways. Our bioinformatics analysis showed that the alteration in intercellular communications involving DaNs might be a previously underestimated aspect of PD pathogeneses with novel translational potential.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease (ND) worldwide (Ascherio and Schwarzschild, 2016)
The microglia cluster (MIG) is annotated with OLR1 and CSF1R, and its genes are enriched in immune response and immune cell activation, phagocytosis, endocytosis, viral and bacterial infection, chemokine signaling, etc
We found that microglia and astrocyte population were significantly increased in PD sample compared with control sample (Supplementary Figures 4B,C; Mann–Whitney test, p = 0.0002 for microglia, p = 0.0020 for astrocyte)
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease (ND) worldwide (Ascherio and Schwarzschild, 2016). The heterogeneous etiology of PD is not fully understood, and the interplay between aging, environmental and genetics factors was proposed to be responsible (Pang et al, 2019). The pathology of PD is characterized with the intracellular α-synucleincontaining inclusion called Lewy body and the progressive loss of dopaminergic neurons (DaNs) in Intercellular Communication in Parkinson’s Disease the substantia nigra (SN) (Dinter et al, 2020). In the course of PD, the primary victims DaNs suffer multiple intracellular dysfunctions and deregulation, including but not limited to mitochondria dysfunction, oxidative stress, autophagic dysfunction, α-synuclein aggregation and so on (reviewed in Subramaniam and Chesselet, 2013; Xilouri et al, 2016; Hou et al, 2020). Despite a considerable leap forward in decoding these mechanisms, they did not yield much in translatable diagnostic and therapeutic strategies, leaving a giant gap between basic science and clinical application
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