The role of microglial activation and neuroinflammation has recently emerged as a potential mediator and /or potentiator of Parkinson's disease (PD) pathogenesis. While the precise mechanisms and pathways responsible for neurodegeneration are relatively unclear, sufficient evidence has been put forth to suggest that PD has a multifactorial etiopathogenesis. Indeed, environmental as well as genetic factors have been demonstrated to cause activation of microglia, leading to neuroinflammation and subsequent damage to the nigrostriatal dopamine system. Furthermore, genetic and environmental insults both involve activation of NADPH oxidase (PHOX), a key mediator of the neurotoxic response following microglial activation. These data highlight the importance of PHOX and provides a common link between genetic susceptibility and environmental insult in the development of PD. Thus, this proposal will exploit the intersection of genetic and environmental factors at PHOX to gain a better understanding of the mechanisms involved in microglia- mediated neurotoxicity. Through the utilization of in vitro and in vivo models, the aims proposed will systematically elucidate the interplay between endogenous and exogenous insults and their synergistic contribution to microglial activation and neurodegeneration. Moreover, specific interacting proteins and pathways involved in these processes will be examined and these results will be further validated in human tissue from PD patients and compared to other neurodegenerative diseases. Completion of these proposed aims will provide a better understanding of the interaction of genetic and environmental factors at PHOX. Finally, the identification of specific proteins and pathways involved in microglia-mediated neurodegeneration may provide potential targets of therapeutic intervention for patients with PD.

Public Health Relevance

This project investigates the potential interplay between genetic vulnerability and environmental exposure that likely contributes to the development of the majority of Parkinson's cases. Elucidation of the mechanisms involved in this interplay may yield new therapies for the devastating disease.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-Y (04))
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Lawler, Cindy P
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University of Washington
Schools of Medicine
United States
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Stewart, Tessandra; Sui, Yu-Ting; Gonzalez-Cuyar, Luis F et al. (2014) Cheek cell-derived *-synuclein and DJ-1 do not differentiate Parkinson's disease from control. Neurobiol Aging 35:418-20
Pan, Catherine; Zhou, Yong; Dator, Romel et al. (2014) Targeted discovery and validation of plasma biomarkers of Parkinson's disease. J Proteome Res 13:4535-45
Stewart, Tessandra; Liu, Changqin; Ginghina, Carmen et al. (2014) Cerebrospinal fluid ?-synuclein predicts cognitive decline in Parkinson disease progression in the DATATOP cohort. Am J Pathol 184:966-75
Shi, Min; Liu, Changqin; Cook, Travis J et al. (2014) Plasma exosomal ?-synuclein is likely CNS-derived and increased in Parkinson's disease. Acta Neuropathol 128:639-50
Zhang, Jing; Mattison, Hayley A; Liu, Changqin et al. (2013) Longitudinal assessment of tau and amyloid beta in cerebrospinal fluid of Parkinson disease. Acta Neuropathol 126:671-82
Korff, Ane; Liu, Changqin; Ginghina, Carmen et al. (2013) ?-Synuclein in cerebrospinal fluid of Alzheimer's disease and mild cognitive impairment. J Alzheimers Dis 36:679-88
Wang, Jian; Hoekstra, Jake G; Zuo, Chuantao et al. (2013) Biomarkers of Parkinson's disease: current status and future perspectives. Drug Discov Today 18:155-62
Mattison, Hayley A; Nie, Hui; Gao, Huiming et al. (2013) Suppressed pro-inflammatory response of microglia in CX3CR1 knockout mice. J Neuroimmunol 257:110-5
Toledo, Jon B; Korff, Ane; Shaw, Leslie M et al. (2013) CSF *-synuclein improves diagnostic and prognostic performance of CSF tau and A* in Alzheimer's disease. Acta Neuropathol 126:683-97
Aasly, J O; Shi, M; Sossi, V et al. (2012) Cerebrospinal fluid amyloid ? and tau in LRRK2 mutation carriers. Neurology 78:55-61

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