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The Journal of Neuroscience, July 23, 2008, 28(30):7687-7698; doi:10.1523/JNEUROSCI.0143-07.2008

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Neurobiology of Disease
Neuroinflammation and Oxidation/Nitration of -Synuclein Linked to Dopaminergic Neurodegeneration

Hui-Ming Gao,¹ Paul T. Kotzbauer,¹ Kunihiro Uryu,¹ Susan Leight,¹ John Q. Trojanowski,^1,2 and Virginia M.-Y. Lee^1,2

¹Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and ²Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Virginia M.-Y. Lee at the above address. Email: vmylee{at}mail.med.upenn.edu

-Synuclein (SYN) is the major component of Lewy bodies, the neuropathological hallmarks of Parkinson's disease (PD). Missense mutations and multiplications of the SYN gene cause autosomal dominant inherited PD. Thus, SYN is implicated in the pathogenesis of PD. However, the mechanism whereby SYN promotes neurodegeneration remains unclear. Familial PD with SYN gene mutations are rare because the majority of PD is sporadic and emerging evidence indicates that sporadic PD may result from genetic and environmental risk factors including neuroinflammation. Hence, we examined the relationship between SYN dysfunction and neuroinflammation in mediating dopaminergic neurodegeneration in mice and dopaminergic neuronal cultures derived from wild-type SYN and mutant A53T SYN transgenic mice in a murine SYN-null (SYNKO) background (M7KO and M83KO, respectively). Stereotaxic injection of an inflammagen, lipopolysaccharide, into substantia nigra of these SYN genetically engineered mice induced similar inflammatory reactions. In M7KO and M83KO, but not in SYNKO mice, the neuroinflammation was associated with dopaminergic neuronal death and the accumulation of insoluble aggregated SYN as cytoplasmic inclusions in nigral neurons. Nitrated/oxidized SYN was detected in these inclusions and abatement of microglia-derived nitric oxide and superoxide provided significant neuroprotection in neuron–glia cultures from M7KO mice. These data suggest that nitric oxide and superoxide released by activated microglia may be mediators that link inflammation and abnormal SYN in mechanisms of PD neurodegeneration. This study advances understanding of the role of neuroinflammation and abnormal SYN in the pathogenesis of PD and opens new avenues for the discovery of more effective therapies for PD.

Key words: -synuclein; dopamine; neuroinflammation; microglia; Parkinson's disease; neurodegeneration

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Received Jan. 12, 2007; revised June 5, 2008; accepted June 19, 2008.

Correspondence should be addressed to Virginia M.-Y. Lee at the above address. Email: vmylee{at}mail.med.upenn.edu

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