Microglia-drive IRF8 upregulates complement pathway in Parkinson's disease

Abstract

Parkinson's disease (PD) is a widespread degenerative disorder of the central nervous system. The gradual degeneration of dopaminergic neurons in the substantia nigra region is one of the primary pathological features of PD. Glial cells in SN are also linked to the pathological PD alterations. To discern the role of neurons and glial cells as well as their corresponding genetic modifications in PD, we utilized diverse bioinformatics techniques and performed biological experiments on cell and animal models. Several transcriptome datasets of the substantia nigra region were collected from the Gene Expression Omnibus dataset. Cibersort was used to deconvolute the data into proportions of brain cell types. WGCNA was used to analyze the association between modules and traits. Machine learning was used to select the hub genes from WGCNA results. Based on the results of transcriptome analysis, microglia were the most related cell type. Through machine learning, IRF8 was identified as the hub gene associated with PD and microglia. Furthermore, an increased ratio of IRF8+ microglia was observed in PD mice, along with an elevated expression of IRF8 in primary microglia cultures treated with α-synuclein preformed fibril (PFFs). To explore the function of IRF8 in microglia under disease condition, we conducted siRNA of IRF8 and found it was highly associated with complement pathway, which may cause the activation of microglia. In conclusion, our research indicated IRF8 may be involved in the functional regulation of microglia in PD.