The involvement of α-synucleinopathy in the disruption of microglial homeostasis contributes to the pathogenesis of Parkinson's disease

• Published in: Cell communication and signaling 2024-01, Vol.22 (1), p.31-19, Article 31
• Main Authors: Miao, Yongzhen, Meng, Hongrui
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; alpha-Synuclein - therapeutic use; Amino acids; Brain; Central nervous system; Cytokines; Dementia; Disease; Disease spread; Genes; Genotype & phenotype; Homeostasis; Humans; Immune clearance; Inflammation; Inflammation - metabolism; Kinases; Lymphocytes; Macrophages; Microglia; Microglia - metabolism; Movement disorders; Mutation; Nervous system; Neurodegenerative diseases; Neurons; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pathogenesis; Pathology; Proteins; Synuclein; Synucleinopathies - metabolism; Synucleinopathies - pathology; Toxicity; α-synuclein
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-023-01402-y

The intracellular deposition and intercellular transmission of α-synuclein (α-syn) are shared pathological characteristics among neurodegenerative disorders collectively known as α-synucleinopathies, including Parkinson's disease (PD). Although the precise triggers of α-synucleinopathies remain unclear, recent findings indicate that disruption of microglial homeostasis contributes to the pathogenesis of PD. Microglia play a crucial role in maintaining optimal neuronal function by ensuring a homeostatic environment, but this function is disrupted during the progression of α-syn pathology. The involvement of microglia in the accumulation, uptake, and clearance of aggregated proteins is critical for managing disease spread and progression caused by α-syn pathology. This review summarizes current knowledge on the interrelationships between microglia and α-synucleinopathies, focusing on the remarkable ability of microglia to recognize and internalize extracellular α-syn through diverse pathways. Microglia process α-syn intracellularly and intercellularly to facilitate the α-syn neuronal aggregation and cell-to-cell propagation. The conformational state of α-synuclein distinctly influences microglial inflammation, which can affect peripheral immune cells such as macrophages and lymphocytes and may regulate the pathogenesis of α-synucleinopathies. We also discuss ongoing research efforts to identify potential therapeutic approaches targeting both α-syn accumulation and inflammation in PD. Video Abstract.