Unraveling the role of neuregulin-mediated astrocytes-OPCs axis in the pathogenesis of age-related macular degeneration and Parkinson’s disease

Abstract

Age-related macular degeneration (AMD) and Parkinson’s disease (PD) are prevalent and debilitating conditions that lead to irreversible blindness and dyskinesia, respectively. Emerging evidences imply that retinal abnormalities may serve as early indicators for monitoring PD. This study endeavors to explore the complex interactions and focus on their shared molecular and pathological mechanisms. We employed a comprehensive approach by integrating single-cell RNA sequencing (scRNA-seq) datasets, obtained from dry AMD retinas and PD brain tissues, along with Weighted Gene Co-expression Network Analysis (WGCNA)-related computational analysis. Gene Set Enrichment Analysis (GSEA) was conducted to analyze PD-related genes within retinal ganglion cells in dry AMD. Cell-cell chat was utilized to predict intercellular communication and signaling pathways. Module eigengenes (MEs) were calculated to identify specific gene modules. Dysregulation of PALLD, FYN and ZMZ1 may lead to cell structural abnormalities, impaired mitochondrial functions, and increased susceptibility to neuroinflammation, contributing to the AMD and PD progression. Additionally, this study highlighted an astrocyte–oligodendrocyte precursor cell (OPCs) signaling axis mediated by Neuregulin (NRG), which is hypothesized to influence neuroinflammatory processes characteristic of dry AMD and PD pathogenesis. Notably, ME-salmon module associated with gene dysregulation exhibited a strong positive correlation with the ME-blue module, linked to neurodegenerative impairment, and the ME-yellow module, related to mitochondrial dysfunction. The comprehensive investigation on astrocytes-OPCs signaling axis, and the NRG signaling pathway advances our understanding of the intricate biological processes underpinning AMD and PD. This research underscores the critical importance about exploring glial-related cell interactions, providing valuable insights into potential novel therapeutic approaches for these complex diseases.