Glial Cell Senescence Impairs α-Synuclein Clearance, Contributing to Parkinson’s Disease
Parkinson’s disease occurs due to the spread of misfolded α-synuclein and associated toxicity. The immune system struggles to defend against this issue, as cellular senescence and inflammatory signaling in the brain’s supporting cells dampen the immune response to protein aggregates in the central nervous system. Aging and the accumulation of senescent glial cells in the brain contribute to Parkinson’s disease progression by inducing chronic neuroinflammatory processes. This study investigates how aging and glial senescence affect the capacity of α-synuclein clearance, providing new insights into the role of senescent glia in Parkinson’s disease pathogenesis.
Parkinson’s disease (PD) is characterized by the pathological accumulation of α-synuclein (α-syn) and the loss of dopaminergic neurons in the substantia nigra. Aging, a significant risk factor for PD, contributes to the progression of the disease through the accumulation of senescent glial cells in the aged brain, inducing chronic neuroinflammatory processes. However, the insufficient degradation of α-syn aggregates and the alteration in the ability of α-syn clearance in senescent glia have received little attention. This study found that aged mice exhibited greater accumulation of human α-synuclein (hu-α-syn) pathology compared to younger mice, and aged microglia showed greater accumulation of hu-α-syn than younger microglia. Furthermore, the study revealed that the clearance of hu-α-syn was primarily dependent on the autophagy-lysosome system and was diminished in senescent glia due to autophagy-lysosome system dysfunction. The study highlights the role of senescent glia in PD pathogenesis.
Link: https://doi.org/10.1038/s41420-024-01816-8
