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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016873-04
Application #
8435443
Study Section
Special Emphasis Panel (ZRG1-BDCN-Y (04))
Program Officer
Lawler, Cindy P
Project Start
2010-03-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$340,540
Indirect Cost
$122,245
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Wang, Shijun; Chu, Chun-Hsien; Guo, Mingri et al. (2016) Identification of a specific α-synuclein peptide (α-Syn 29-40) capable of eliciting microglial superoxide production to damage dopaminergic neurons. J Neuroinflammation 13:158
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
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
Wang, Shijun; Chu, Chun-Hsien; Stewart, Tessandra et al. (2015) α-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation. Proc Natl Acad Sci U S A 112:E1926-35
Searles Nielsen, Susan; Checkoway, Harvey; Zhang, Jing et al. (2015) Blood α-synuclein in agricultural pesticide handlers in central Washington State. Environ Res 136:75-81
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
Jiang, Tianfang; Hoekstra, Jake; Heng, Xin et al. (2015) P2X7 receptor is critical in α-synuclein--mediated microglial NADPH oxidase activation. Neurobiol Aging 36:2304-18

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