α-synuclein in activated microglias during infarct-induced Wallerian degeneration.

Abnormal aggregation of α-Synuclein (αS) drives cell loss and produces intracellular inclusions in synucleinopathies, which may be due to insufficient degradation resulting from either a dysfunctional ubiquitin-proteasome system (UPS) or a constant production of mutated αS that overwhelms the UPS. Recent in vitro studies suggest that the autophagylysosome pathway is also involved in αS degradation. On the other hand, synucleinopathies are associated with microglial activation and infiltration. In this postmortem study, we aimed to investigate the relationship between microglial activity and αS disposition in serial patients with cerebral infarct-induced Wallerian degeneration (CI-WD) of the corticospinal fibers. Immunoreactivity for αS was found in activated microglias localized in the CI-WD regions of seven patients (mean 65.6 ± 9.3 years), but not five neuropathologically normal subjects (mean 70.4 ± 8.0 years). No immunoreactivity for ubiquitin or neurofilament protein was present in the microglias. Confocal analysis of double-immunofluorescence staining confirmed the colocalization of αS with the microglial marker. Our results suggest endocytosis (phagocytosis and/or pinocytosis) of αS into activated microglias during the process of CI-WD. This finding indicates that αS may alternatively undergo microglia-associated lysosomal proteolysis for degradation. [ABSTRACT FROM AUTHOR]