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

作者：Stefanova Nadia^*; Fellner Lisa; Reindl Markus; Masliah Eliezer; Poewe Werner; Wenning Gregor K

来源：American Journal Of Pathology, 2011, 179(2): 954-963.

DOI：10.1016/j.ajpath.2011.04.013

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 neuro-degeneration. 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. (Am J Pathol 2011, 179:954-963; DOI: 10.1016/j.ajpath.2011.04.013)

• 出版日期2011-8