Parkinson's disease (PD) is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) with accumulation of a-synuclein (a-syn) in aggregates and Lewy bodies. Oxidative stress is implicated as a causative factor. Nitration of a-syn promotes misfolding and formation of aggregates resistant to clearance by autophagy. Our studies suggest that myeloperoxidase (MPO) is a significant source of oxidants that promote misfolding and aggregation of a-syn, as well as oxidation/nitration of other proteins implicated in the pathology of PD. MPO is a component of the armamentarium of the innate immune system, released by neutrophils and monocytes at sites of infection where it produces the potent oxidant, hypochlorous acid (HOCl) while reacting with nitric oxide to generate reactive nitrating species. MPO oxidants also damage normal cells, such that expression is normally restricted to myeloid precursors. However, the human MPO gene (huMPO) is able to escape this restriction, in that MPO is aberrantly expressed in subsets of neurons and astrocytes in Alzheimer's disease (AD). MPO is also aberrantly expressed in PD SNpc, and in vitro studies showed that MPO promotes nitration of a-syn leading to dimers and oligomers.
The aims of this proposal are to (1) Investigate the oxidative and pathological consequences of MPO expression in mouse models of synucleinopathies. (2) Evaluate human PD tissue to establish the expression patterns of MPO and the oxidative consequences. (3) Investigate the role of MPO in synucleinopathies in vitro using SHSY5Y neuroblastoma cells stably expressing a-syn.

Public Health Relevance

Current treatments for Parkinson's disease ameliorate the symptoms but do not reduce the progressive loss of neurons. These studies may provide evidence that MPO oxidants contribute to PD pathology, identifying MPO as a novel therapeutic target. Screening studies could identify small molecule antagonists that reduce neurological damage if provided at early stages of PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS074303-04
Application #
8686093
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Sutherland, Margaret L
Project Start
2011-09-15
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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