The overall objective of our research is to identify and validate novel targets for the treatment of Parkinson's disease (PD). PD is characterized by loss of dopaminergic neurons, which are especially vulnerable to oxidative stress. Glutaredoxin (Grx) is an antioxidant defense enzyme that counteracts oxidative stress and maintains thiol homeostasis by catalyzing the reversible formation of protein-glutathione mixed disulfides on cysteine residues (protein-SSG). This oxidative modification is implicated in change of function for many proteins involved in cell survival, including proteins that have been previously identifie with familial forms of PD. Using C. elegans as a model organism, we have found that deficiency in the nematode homolog of Grx1, the major isoform of Grx in mammals, leads to exacerbation of dopaminergic degeneration elicited by overexpression of mutant LRRK2 (G2019S or R1441C), ?-synuclein, or tyrosine hydroxylase. These findings indicate that Grx1 deficiency can predispose to PD-relevant phenotype in an animal model, suggesting that Grx1 deficiency contributes to PD pathogenesis. Supporting the relevance of these genetic models, we have obtained preliminary evidence that Grx1 content is decreased in postmortem brains of PD patients. Accordingly, we propose to characterize and validate the neuroprotective role of Grx1 in mammalian models of PD, and to investigate whether changes in glutathionylation status of key proteins implicated in familial PD also contribute importantly to the disease pathogenesis. To examine if Grx1 deficiency confers vulnerability to dopaminergic degeneration in mammals, we propose in Aim 1 to characterize a novel mouse model generated from crossing existing transgenic human LRRK2 mutant animals with Grx1-knockout animals. The transgenic LRRK2 mutant mice with Grx1-knockout represent a genetically engineered mammalian animal model of elevated oxidative stress and specific deficiency in thiol homeostasis. We will determine whether this novel mouse model manifests loss of dopaminergic neurons characteristic of PD. The outcome of this study would validate if Grx1 serves as a critical regulator of PD pathogenesis.
In Aim 2, we will identify oxidative cysteine modifications and changes in function of the proteins implicated in PD pathogenesis including ?-synuclein, parkin, UCH-L1, DJ-1, PINK1, and LRRK2. The contribution of cysteine modifications to PD-like phenotype will be examined by the use of non-oxidizable mutant forms of the proteins in mammalian cell and C. elegans models of PD. Correspondence between susceptibility to neurodegeneration and oxidative modification of proteins implicated in familial PD would provide an important advance in understanding pathogenic mechanisms underlying sporadic PD.

Public Health Relevance

Parkinson's disease (PD) is a devastating and eventually fatal brain disorder affecting millions of people worldwide. The current therapeutic options for PD are very limited and no cure exists for the disease. The goal of our studies is to identify neuroprotective factors vital to the survival of the brain cells affected in PD. The significance o our proposed research will be the possibility of discovering novel targets for the treatment and prevention of PD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Cell Death and Injury in Neurodegeneration Study Section (CDIN)
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Sieber, Beth-Anne
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Case Western Reserve University
Schools of Medicine
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Gorelenkova Miller, Olga; Cole, Kyle S; Emerson, Corey C et al. (2017) Novel chloroacetamido compound CWR-J02 is an anti-inflammatory glutaredoxin-1 inhibitor. PLoS One 12:e0187991
Johnson, William M; Golczak, Marcin; Choe, Kyonghwan et al. (2016) Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson's Disease. Biochemistry 55:4519-32
Gorelenkova Miller, Olga; Behring, Jessica Belle; Siedlak, Sandra L et al. (2016) Upregulation of Glutaredoxin-1 Activates Microglia and Promotes Neurodegeneration: Implications for Parkinson's Disease. Antioxid Redox Signal 25:967-982
Johnson, William M; Yao, Chen; Siedlak, Sandra L et al. (2015) Glutaredoxin deficiency exacerbates neurodegeneration in C. elegans models of Parkinson's disease. Hum Mol Genet 24:1322-35
Johnson, William M; Wilson-Delfosse, Amy L; Chen, Shu G et al. (2015) The roles of redox enzymes in Parkinson's disease: Focus on glutaredoxin. Ther Targets Neurol Dis 2: