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
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Stewart, Tessandra; Sossi, Vesna; Aasly, Jan O et al. (2015) Phosphorylated α-synuclein in Parkinson's disease: correlation depends on disease severity. Acta Neuropathol Commun 3:7
Hoekstra, Jake G; Cook, Travis J; Stewart, Tessandra et al. (2015) Astrocytic dynamin-like protein 1 regulates neuronal protection against excitotoxicity in Parkinson disease. Am J Pathol 185:536-49
Shi, Min; Movius, James; Dator, Romel et al. (2015) Cerebrospinal fluid peptides as potential Parkinson disease biomarkers: a staged pipeline for discovery and validation. Mol Cell Proteomics 14:544-55
Liu, Changqin; Cholerton, Brenna; Shi, Min et al. (2015) CSF tau and tau/Aβ42 predict cognitive decline in Parkinson's disease. Parkinsonism Relat Disord 21:271-6

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