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)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES019277-05
Application #
8843432
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Hollander, Jonathan
Project Start
2011-09-01
Project End
2016-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
5
Fiscal Year
2015
Total Cost
$345,038
Indirect Cost
$120,038
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Criswell, Susan R; Nielsen, Susan Searles; Warden, Mark et al. (2018) [18F]FDOPA positron emission tomography in manganese-exposed workers. Neurotoxicology 64:43-49
Matsumoto, Junichi; Stewart, Tessandra; Sheng, Lifu et al. (2017) Transmission of ?-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson's disease? Acta Neuropathol Commun 5:71
Pottiez, Gwënaël; Yang, Li; Stewart, Tessandra et al. (2017) Mass-Spectrometry-Based Method To Quantify in Parallel Tau and Amyloid ? 1-42 in CSF for the Diagnosis of Alzheimer's Disease. J Proteome Res 16:1228-1238
Shi, Min; Kovac, Andrej; Korff, Ane et al. (2016) CNS tau efflux via exosomes is likely increased in Parkinson's disease but not in Alzheimer's disease. Alzheimers Dement 12:1125-1131
Wang, Shijun; Chu, Chun-Hsien; Guo, Mingri et al. (2016) Identification of a specific ?-synuclein peptide (?-Syn 29-40) capable of eliciting microglial superoxide production to damage dopaminergic neurons. J Neuroinflammation 13:158
Cook, Travis J; Hoekstra, Jake G; Eaton, David L et al. (2016) Mortalin is Expressed by Astrocytes and Decreased in the Midbrain of Parkinson's Disease Patients. Brain Pathol 26:75-81
Atik, Anzari; Stewart, Tessandra; Zhang, Jing (2016) Alpha-Synuclein as a Biomarker for Parkinson's Disease. Brain Pathol 26:410-8
Liu, Changqin; Cholerton, Brenna; Shi, Min et al. (2015) CSF tau and tau/A?42 predict cognitive decline in Parkinson's disease. Parkinsonism Relat Disord 21:271-6
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
Criswell, Susan R; Nelson, Gill; Gonzalez-Cuyar, Luis F et al. (2015) Ex vivo magnetic resonance imaging in South African manganese mine workers. Neurotoxicology 49:8-14

Showing the most recent 10 out of 33 publications