Glial senescence enhances -synuclein pathology owing to its insufficient clearance caused by autophagy dysfunction

Parkinson's disease (PD) is characterized by the pathological accumulation of alpha-synuclein (alpha-syn) and loss of dopaminergic neurons in the substantia nigra. Aging is a significant risk factor for PD. The accumulation of senescent glial cells in the aged brain contributes to PD progression by inducing chronic neuroinflammatory processes. However, although the insufficient degradation of alpha-syn aggregates results in PD deterioration, the possible alteration in the ability of alpha-syn clearance in senescent glia has received little attention. In this study, we investigated how aging and glial senescence affect the capacity of alpha-syn clearance. We found that following the intra-striatal injection of human alpha-syn (hu-alpha-syn) preformed fibril, hu-alpha-syn pathology persisted more in aged mice compared with younger mice and that aged microglia exhibited greater accumulation of hu-alpha-syn than younger microglia. Moreover, in vitro assay revealed that the clearance of hu-alpha-syn was primarily dependent on the autophagy-lysosome system rather than on the ubiquitin-proteasome system and that the capacity of hu-alpha-syn clearance was diminished in senescent glia because of autophagy-lysosome system dysfunction. Overall, this study provides new insights into the role of senescent glia in PD pathogenesis.