Oxidative stress and mitochondrial dysfunction are centrally involved in the etiology of several diseases and in the normal process of aging. The protein DJ-1 is an oxidative stress response protein whose absence or dysregulation has been implicated in parkinsonism, cancer, and stroke. DJ-1 can robustly protect cells against multiple forms of oxidative stress and thereby confer protection against degeneration that can lead to disease. The molecular mechanism(s) of DJ-1's action, however, remains unclear. DJ-1 contains a functionally essential cysteine residue whose oxidation is hypothesized to regulate its cytoprotective function. We will investigate the mechanism by which DJ-1 senses and responds to oxidative stress by accomplishing three specific aims.
The first aim will investigate the role of DJ-1 cysteine oxidation in the protection against oxidative stress in the Drosophila animal model system. We will combine X-ray crystallography, biochemistry, and Drosophila genetics to establish a powerful animal model for the redox regulation of DJ-1 function.
The second aim will determine the structure-function relationships for an established mRNA binding activity of DJ-1. The results will be used to test the hypothesis that conserved structural features near the oxidized cysteine integrate the RNA binding and redox sensing functions of DJ-1.
The third aim will use a prokaryotic model system to investigate the evolutionarily conserved mechanism of DJ-1 protective function. The results will be used to test existing hypotheses about the conservation of regulatory cysteine oxidation in DJ-1 function as well as discover new functions for DJ-1. In total, the proposed research will provide a comprehensive molecular basis for understanding the oxidative regulation and pathogenic disruption of DJ-1 function. Ultimately, the results of this research will be used to design a new generation of therapeutics that enhance the protective function of DJ-1 in vulnerable cell types.

Public Health Relevance

Oxidative stress and mitochondrial dysfunction are centrally involved in several human diseases. Major recent advances have identified DJ-1 as a protein that confers robust protection against oxidative stress. The precise biochemical function of DJ-1, however, remains uncertain. The long-term goal of this proposal is to determine the biochemical functions of DJ-1 that confer protection against oxidative stress and with the goal of developing therapies that improve the protective function of DJ-1.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Anderson, Vernon
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University of Nebraska Lincoln
Schools of Earth Sciences/Natur
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Catazaro, Jonathan; Andrews, Tessa; Milkovic, Nicole M et al. (2017) 15N CEST data and traditional model-free analysis capture fast internal dynamics of DJ-1. Anal Biochem 542:24-28
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