Both genetic vulnerability and environmental exposure have been linked to the development of idiopathic Parkinson's disease (PD);however, the precise mechanisms by which these two factors intercept remain elusive. This proposal is designated to explore a potential link between genetic susceptibility and environmental factors - a tight coupling between microglial Mac1 and NADPH oxidase, both are membrane proteins critically involved in microglial activation which is a hallmark of neuroinflammation. The mechanisms involved in microglial activation are not understood completely. While some components of neuroinflammation can also be beneficial to neuronal survival, pro- inflammatory factors, especially reactive oxygen species (ROS), when produced in excess, are believed to cause "collateral" damage to the central nervous system. The coupling between Mac1 and NADPH oxidase enzyme appears to be one of the major sources of pro-inflammatory ROS causing neural damage. More importantly, the action of many endogenous toxins and exogenous neurotoxicants seems to converge on the activation of Mac1-NADPH oxidase pathway. Thus, this proposal will be centered on the coupling of these two proteins, with the use of various in vitro and in vivo experimental systems, to examine the detailed mechanisms by which genetic susceptibility (modeled by mutations of -synuclein gene) interact with parkinsonian toxicants via Mac1-NADPH oxidase coupling. Additionally, contribution of astroglia to microglial activation will also be explored. Finally, we will investigate novel and specific inhibitors that block Mac1 and/or NADPH oxidase, thereby providing new therapies to inhibit pro-inflammatory factors specifically while sparing neuroprotective elements of neuroinflammation, to slow down the progression of PD.

Public Health Relevance

This project investigates the roles of Mac1-NADPH oxidase in a potential interplay between genetic vulnerability and environmental exposure as well as new therapies for Parkinson's disease, a devastating progressive neurodegenerative disorder that is currently without cure.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01ES019277-04
Application #
8663695
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Hollander, Jonathan
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
Gonzalez-Cuyar, Luis F; Nelson, Gill; Criswell, Susan R et al. (2014) Quantitative neuropathology associated with chronic manganese exposure in South African mine workers. Neurotoxicology 45:260-6
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

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