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- Title
Aggregated α-synuclein activates microglia: a process leading to disease progression in Parkinson's disease.
- Authors
Wei Zhang; Tongguang Wang; Zhong Pei; Miller, David S.; Block, Michelle L.; Wilson, Belinda; Jau-Shyong Hong; Xuefei Wu; Wanqin Zhang; Yong Zhou; Jing Zhang
- Abstract
A growing body of evidence indicates that an inflammatory process in the substantia nigra, characterized by activation of resident microglia, likely either initiates or aggravates nigral neurodegeneration in Parkinson's disease (PD). To study the mechanisms by which nigral microglia are activated in PD, the potential role of α-synuclein (a major component of Lewy bodies that can cause neurodegeneration when aggregated) in microglial activation was investigated. The results demonstrated that in a primary mesencephalic neuron-glia culture system, extracellular aggregated human α-synuclein indeed activated microglia; microglial activation enhanced dopaminergic neurodegeneration induced by aggregated α-synuclein. Furthermore, microglial enhancement of α-synuclein-mediated neurotoxicity depended on phagocytosis of α-synuclein and activation of NADPH oxidase with production of reactive oxygen species. These results suggest that Nigeria neuronal damage, regardless of etiology, may release aggregated α-synuclein into substantia nigra, which activates microglia with production of proinflammatory mediators, thereby leading to persistent and progressive nigral neurodegeneration in PD. Finally, NADPH oxidase could be an ideal target for potential pharmaceutical intervention, given that it plays a critical role in α-synuclein-mediated microglial activation and associated neurotoxicity.
- Subjects
MICROGLIA; PHAGOCYTOSIS; NATURAL immunity; AGING; OXIDATIVE stress; PARKINSON'S disease; INFLAMMATION
- Publication
FASEB Journal, 2005, Vol 19, Issue 6, p533
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.04-2751com