Toll-Like Receptor 4 Promotes alpha-Synuclein Clearance and Survival of Nigral Dopaminergic Neurons.

摘要

Toll-like receptors (TLRs) mediate innate immunity, and their dysregulation may play a role in alpha-synucleinopathies, such as Parkinson's disease or multiple system atrophy (MSA). The aim of this study was to define the role of TLR4 in alpha-synuclein-linked neurodegeneration. Ablation of TLR4 in a transgenic mouse model of MSA with oligodendroglial alpha-synuclein overexpression augmented motor disability and enhanced loss of nigrostriatal dopaminergic neurons. These changes were associated with increased brain levels of alpha-synuclein linked to disturbed TLR4-mediated microglial phagocytosis of alpha-synuclein. Furthermore, tumor necrosis factor-alpha levels were increased in the midbrain and associated with a proinflammatory astroglial response. Our data suggest that TLR4 ablation impairs the phagocytic response of microglia to alpha-synuclein and enhances neurodegeneration in a transgenic MSA mouse model. The study supports TLR4 signaling as innate neuroprotective mechanism acting through clearance of alpha-synuclein.