Glial Cell Senescence Impairs α-Synuclein Clearance, Contributing to Parkinson's Disease

Parkinson's disease arises from the spread of misfolded α-synuclein and associated toxicity. α-synuclein is one of the few proteins in the body capable of misfolding in ways that encourage other molecules of the same protein to also misfold, forming solid aggregates and a surrounding halo of altered biochemistry that changes cell behavior for the worse, or kills those cells. The immune system is capable of mounting a defense against this sort of issue, but as noted here, the immune response to protein aggregates in the central nervous system is dampened by an increasing burden of cellular senescence and inflammatory signaling in the supporting cells of the brain.

Parkinson's disease (PD) is characterized by the pathological accumulation of α-synuclein (α-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 α-syn aggregates results in PD deterioration, the possible alteration in the ability of α-syn clearance in senescent glia has received little attention.

In this study, we investigated how aging and glial senescence affect the capacity of α-syn clearance. We found that following the intra-striatal injection of human α-syn (hu-α-syn) preformed fibril, hu-α-syn pathology persisted more in aged mice compared with younger mice and that aged microglia exhibited greater accumulation of hu-α-syn than younger microglia. Moreover, in vitro assay revealed that the clearance of hu-α-syn was primarily dependent on the autophagy-lysosome system rather than on the ubiquitin-proteasome system and that the capacity of hu-α-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.


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