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Microglial PHOX and Mac‐1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha‐synuclein
Abstract
α‐Synuclein, a gene whose mutations, duplication, and triplication has been linked to autosomal dominant familial Parkinson's disease (fPD), appears to play a central role in the pathogenesis of sporadic PD (sPD) as well. Enhancement of neurodegeneration induced by mutant α‐synuclein has been attributed to date largely to faster formation of α‐synuclein aggregates in neurons. Recently, we reported that microglial activation enhances wild type (WT) α‐synuclein‐elicited dopaminergic neurodegeneration. In the present study, using a primary mesencephalic culture system, we tested whether mutated α‐synuclein could activate microglia more powerfully than WT α‐synuclein, thereby contributing to the accelerated neurodegeneration observed in fPD. The results showed that α‐synuclein with the A30P or A53T mutations caused greater microglial activation than WT α‐synuclein. Furthermore, the extent of microglial activation paralleled the degree of dopaminergic neurotoxicity induced by WT and mutant α‐synuclein. Mutant α‐synuclein also induced greater production of reactive oxygen species than WT α‐synuclein by NADPH oxidase (PHOX), and PHOX activation was linked to direct activation of macrophage antigen‐1 (Mac‐1) receptor, rather than α‐synuclein internalization via scavenger receptors. These results have, for the first time, demonstrated that microglia are also critical in enhanced neurotoxicity induced by mutant α‐synuclein. © 2007 Wiley‐Liss, Inc.
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Metadata
- Authors
- Zhang, W., Dallas, S., Zhang, D., Guo, J., Pang, H., Wilson, B., Miller, D. S., Chen, B., Zhang, W., McGeer, P. L., Hong, J., & Zhang, J.
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2007-06-28
- Volume
- 55
- Issue
- 11
- Pages
- 1178-1188
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- OpenAlex
- W2095376584
- Cited by
- 160
- References
- 10
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Open access
- closed
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- Zhang, W., Dallas, S., Zhang, D., Guo, J., Pang, H., Wilson, B., Miller, D. S., Chen, B., Zhang, W., McGeer, P. L., Hong, J., & Zhang, J. (2007). Microglial PHOX and Mac‐1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha‐synuclein. Glia. https://doi.org/10.1002/glia.20532
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