Parkinson's disease (PD) is a progressive neurodegenerative disorder underscored by the gradual loss of dopaminergic neurons in disease-inflicted brains. The major inclusion in degenerating dopaminergic cells (Lewy bodies) contains aggregates of the a-synuclein (a-syn) protein. The Fe(III) concentration in the cytoplasm of dopaminergic cells and Cu(II) content in cerebral spinal fluid of PD patients are both elevated. The oxidative stress hypothesis, which contends that complexes formed between a-syn and redox active metal ions could impose oxidative stress on neuronal cells, has gained widespread attention. The broad, long-term objective of this proposal is to rationalize the various redox reactions involving a-syn-metal complexes and cytosolic species (e.g., dopamine, glutathione, and ascorbic acid) in the development of oxidative stress and damage. The motivation behind the proposed study is that the inconsistencies in the current oxidative stress hypothesis stem largely from the lack of knowledge of the redox potentials of the a-syn-metal complexes and a detailed understanding of the reactions that produce reactive oxygen species (ROS).
The specific aims i nclude (1) studying the binding of Fe(III) and Cu(II) to wild-type and mutant a-syn molecules and the redox properties of the resultant complexes, (2) probing the kinetics of the ROS-producing reactions that involve these a-syn-metal complexes, and (3) examining the aggregation behaviors of a-syn in the presence of Fe(III) or Cu(II) and evaluating the neurotoxicity of the resultant aggregates. The kinetic studies of the a-syn-metal complexes or metal-containing a-syn aggregates in the presence of exogenous species (e.g., antioxidants such as flavonoids or PD risk factors such as herbicides) will also be conducted. A variety of analytical techniques (e.g., NMR, EPR, voltammetry, fluorescence, and adsorption spectroscopy) will be used to investigate the binding and redox reactions, whereas atomic force microscopy, circular dichroism, and dynamic light scattering will be employed to follow the aggregation processes.

Public Health Relevance

The study will provide insight into the possible roles played by Fe(III), Cu(II), and a-synuclein in the etiology of Parkinson's disease (PD). The results are expected to lead to a better understanding of the associated molecular mechanisms, the modification of which might prevent or alleviate the neuropathological effects of PD. Furthermore, given the variety of techniques proposed and the interdisciplinary nature of this high-impact research, the work will play a significant part in training the next generation of researchers at a minority-serving institution.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Enhancement Award (SC1)
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Special Emphasis Panel (ZGM1-MBRS-X (CH))
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Sutherland, Margaret L
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California State University Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Kai, Tianhan; Zhang, Lin; Wang, Xiaoying et al. (2015) Tabersonine inhibits amyloid fibril formation and cytotoxicity of A?(1-42). ACS Chem Neurosci 6:879-88
He, Yonghui; Liu, Mengmeng; Darabedian, Narek et al. (2014) pH-dependent coordination of Pb2+ to metallothionein2: structures and insight into lead detoxification. Inorg Chem 53:2822-30
Zhou, Miao; Yang, Minghui; Zhou, Feimeng (2014) Paper based colorimetric biosensing platform utilizing cross-linked siloxane as probe. Biosens Bioelectron 55:39-43
Yang, Minghui; Yi, Xinyao; Wang, Jianxiu et al. (2014) Electroanalytical and surface plasmon resonance sensors for detection of breast cancer and Alzheimer's disease biomarkers in cells and body fluids. Analyst 139:1814-25
Harrington, Michael G; Chiang, Jiarong; Pogoda, Janice M et al. (2013) Executive function changes before memory in preclinical Alzheimer's pathology: a prospective, cross-sectional, case control study. PLoS One 8:e79378
Yi, Xinyao; Han, Hongxing; Zhang, Yu et al. (2013) Amplified voltammetric characterization of cleavage of the biotinylated peptide by BACE1 and screening of BACE1 inhibitors. Biosens Bioelectron 50:224-8
Zhou, Binbin; Hao, Yuanqiang; Wang, Chengshan et al. (2013) Conversion of natively unstructured ?-synuclein to its ?-helical conformation significantly attenuates production of reactive oxygen species. J Inorg Biochem 118:68-73
Shi, Shuyun; Zhao, Binqing; Yagnik, Gargey et al. (2013) An interface for sensitive analysis of monoamine neurotransmitters by ion-pair chromatography-electrospray ionization-mass spectrometry with continuous online elimination of ion-pair reagents. Anal Chem 85:6598-602
Yu, Xiang; Wang, Qiuming; Pan, Qingfen et al. (2013) Molecular interactions of Alzheimer amyloid-? oligomers with neutral and negatively charged lipid bilayers. Phys Chem Chem Phys 15:8878-89
Jiang, Dianlu; Shi, Shuyun; Zhang, Lin et al. (2013) Inhibition of the Fe(III)-catalyzed dopamine oxidation by ATP and its relevance to oxidative stress in Parkinson's disease. ACS Chem Neurosci 4:1305-13

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