Several different, seemingly unrelated processes can cause Parkinson?s disease (PD). For examples, genetic mutations that affect ?-synuclein expression, proteasome function, and mitochondrial quality control each produce a disease phenotype indistinguishable from toxin-induced and ?idiopathic? PD. A fundamental question is whether these disparate processes act through independent mechanisms to produce the same disease phenotype, or whether instead these processes converge to a shared pathogenic process. The question is important because identification of a shared pathogenic process could provide an approach for slowing the progression of idiopathic PD. Here we propose that neuronal glutathione is a critical nexus linking these processes, by virtue of its roles in both protein folding / repair and rapid scavenging of reactive oxygen species (ROS). We will test the hypothesis that ?-synuclein overexpression (or aggregation) causes neuronal glutathione depletion and resultant neurodegeneration by facilitating metal-catalyzed ROS production. The studies will use genetic and pharmacological approaches in mouse and cell culture models of PD. The Thy-1 ?-synuclein mouse, which exhibits several features of PD, will be crossed with mice having genetically reduced neuronal glutathione levels. The progeny and founder stains will be evaluated at serial time points with measures of motor function, neuronal glutathione content, oxidative stress, and ?-synuclein aggregation. We will also use these mice stains to evaluate a pharmacological approach for augmenting neuronal glutathione levels and slowing disease progression. The pharmacological studies will provide a complementary test of the underlying hypotheses, and will additionally provide preclinical efficacy data. Cerebrospinal fluid from the treated mice will be collected for a metabolomics assessment of potential treatment biomarkers. In parallel with these in vivo studies, we will use a cell culture system to more directly evaluate processes by which ?- synuclein overexpression or aggregation may promote ROS production and glutathione consumption. These processes include ?-synuclein interactions with dopamine, pre-formed ?-synuclein fibrils, and protein chaperones. Central to these studies is the concept that ?-synuclein or ?-synuclein aggregates can promote ROS production through association with transition metals. The studies will employ a dopaminergic SH-SY5 neuroblastoma line in which ?-synuclein expression can be titrated in response to a chemical signal (doxycycline)and, where feasible, cultured midbrain neurons from wild-type and ?- synuclein overexpressing mice.

Public Health Relevance

Approximately 80,000 veterans with Parkinson?s disease (PD) receive care from the Department of Veterans Affairs. Agent Orange and other environmental toxins have been associated with an increased incidence of this disease. Although many symptoms of Parkinson?s disease are treatable, progression of the underlying disease cannot be slowed by any currently available intervention. The present studies aim to improve our understanding of how this disease progresses over time, and to explore a potential treatment approach using animal models of the disease. The studies are based on idea that neuronal accumulation of ?-synuclein leads to consumption of the endogenous antioxidant glutathione, and that drugs which facilitate glutathione synthesis in neurons can improve neuronal survival.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology E (NURE)
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Veterans Affairs Medical Center San Francisco
San Francisco
United States
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Barros, L Felipe; Brown, Angus; Swanson, Raymond A (2018) Glia in brain energy metabolism: A perspective. Glia 66:1134-1137
Connolly, Niamh M C; Theurey, Pierre; Adam-Vizi, Vera et al. (2018) Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases. Cell Death Differ 25:542-572
Berger, Nathan A; Besson, Valerie C; Boulares, A Hamid et al. (2018) Opportunities for the repurposing of PARP inhibitors for the therapy of non-oncological diseases. Br J Pharmacol 175:192-222
Ghosh, Soumitra; Castillo, Erika; Frias, Elma S et al. (2018) Bioenergetic regulation of microglia. Glia 66:1200-1212