Abstract
Parkinson’s disease (PD) is an age-related and second most common neurodegenerative disorder. In recent years, increasing evidence revealed that peripheral immune cells might be able to infiltrate into brain tissues, which could arouse neuroinflammation and aggravate neurodegeneration. This study aimed to illuminate the landscape of peripheral immune cells and signature genes associated with immune infiltration in PD. Several transcriptomic datasets of substantia nigra (SN) from the Gene Expression Omnibus (GEO) database were separately collected as training cohort, testing cohort, and external validation cohort. The immunoscore of each sample calculated by single-sample gene set enrichment analysis was used to reflect the peripheral immune cell infiltration and to identify the differential immune cell types between PD and healthy participants. According to receiver operating characteristic (ROC) curve analysis, the immunoscore achieved an overall accuracy of the area under the curve (AUC) = 0.883 in the testing cohort, respectively. The immunoscore displayed good performance in the external validation cohort with an AUC of 0.745. The correlation analysis and logistic regression analysis were used to analyze the correlation between immune cells and PD, and mast cell was identified most associated with the occurrence of PD. Additionally, increased mast cells were also observed in our in vivo PD model. Weighted gene co-expression network analysis (WGCNA) was used to selected module genes related to a mast cell. The least absolute shrinkage and selection operator (LASSO) analysis and random-forest analysis were used to analyze module genes, and two hub genes RBM3 and AGTR1 were identified as associated with mast cells in the training cohort. The expression levels of RBM3 and AGTR1 in these cohorts and PD models revealed that these hub genes were significantly downregulated in PD. Moreover, the expression trend of the aforementioned two genes differed in mast cells and dopaminergic (DA) neurons. In conclusion, this study not only exhibited a landscape of immune infiltrating patterns in PD but also identified mast cells and two hub genes associated with the occurrence of PD, which provided potential therapeutic targets for PD patients (PDs).
Highlights
Parkinson’s disease (PD) is an age-related and the second most common neurodegenerative disorder characterized clinically by classic motor symptoms, including resting tremor, bradykinesia, rigidity, and non-motor symptoms, including insomnia, constipation, and pathologically by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta and the occurrence of Lewy bodies containing α-synuclein (Cao et al, 2011; Fasano et al, 2015; Kalia and Lang, 2015)
These results suggest that the immune infiltration patterns in SN tissue of PDs might be altered during the progression of the disease
The Logistic regression analysis based on these immune cell types revealed that mast cells were significantly correlated to the occurrence of PD, and the receiver operating characteristic (ROC) curve of mast cells was drawn to assess the predictive accuracy with the area under the curve (AUC) = 0.716 (Figure 3B); and it was already reported that the number and activation of mast cells in PD brain slices had a higher level compared to non-PD control brain slices (Kempuraj et al, 2019)
Summary
Parkinson’s disease (PD) is an age-related and the second most common neurodegenerative disorder characterized clinically by classic motor symptoms, including resting tremor, bradykinesia, rigidity, and non-motor symptoms, including insomnia, constipation, and pathologically by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta and the occurrence of Lewy bodies containing α-synuclein (Cao et al, 2011; Fasano et al, 2015; Kalia and Lang, 2015). Mounting evidence indicates that neuroinflammation is one of the vital features in both PD patients (PDs) and animal models of PD, the hallmarks of which are the presence of activated microglia and astrocyte that occur together with the loss of DA neurons in the midbrain (Cao et al, 2011; Calabrese et al, 2018; Stephenson et al, 2018). Microglia and astrocyte could be activated by multiple factors related to PD, such as the pivotal PD-associated genes [α-synuclein (SNCA), Parkin, deglycase (DJ-1), leucine-rich repeat kinase 2 (LRRK2)] and neurotoxins (rotenone and methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Wang et al, 2015). Neuroinflammation may play significant roles in pathogenetic mechanisms of PD, including the deposition of protein aggregates, injury of oxidative stress, impairment of mitochondrial function, disruption of calcium homeostasis, and abnormal iron deposition (He et al, 2020; Picca et al, 2020)
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