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How alpha-Synuclein causes Parkinson’s-Associated Neural Damage

Jing Zhang, M.D., Ph.D.
University of Washington
NIEHS Grant R01ES019277

New research, funded in part by NIEHS, has revealed key insights into how alpha-synuclein aggregates cause damage to neurons in diseases such as Parkinson’s disease. The research also revealed a possible new therapeutic strategy that might prevent the progressive neuron loss of Parkinson’s disease.

In Parkinson’s disease, alpha-synuclein aggregates released from neurons activate immune cells known as microglia, leading to chronic neuroinflammation that damages neurons. Using cultured rat cells, the researchers conducted experiments to find out more about how alpha-synuclein affects microglial activity. They also studied why microglia migrate toward injured neurons and tend to accumulate with alpha-synuclein aggregates in the affected areas of Parkinson’s disease brains, such as the substantia nigra.

The experiments showed that neuron-derived alpha-synuclein aggregates act as chemoattractants that direct microglial migration by acting on NADPH oxidase and several downstream proteins. Blocking the targets involved in alpha-synuclein–mediated microglial directional migration could protect against progressive neuronal loss, representing a potential therapeutic strategy for Parkinson’s disease and other diseases involving alpha-synuclein aggregates.

Citation: Wang S, Chu CH, Stewart T, Ginghina C, Wang Y, Nie H, Guo M, Wilson B, Hong JS, Zhang J. 2015. α-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation. Proc Natl Acad Sci U S A 112(15):E1926- E1935.