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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center


William M. Valentine, D.V.M, , Ph.D.

Associate Professor of Pathology, Microbiology and Immunology

Contact Information:

Vanderbilt University Medical Center
1161 21st Ave, C-3321A MCN
Nashville, TN 37232-2561
Fax: 615-343-9825

Research Description

Parkinson disease (PD) is the second most common neurodegenerative disease and the prevalence of PD is predicted to double in the US and more than double in developing countries during the next 25 years; however a definite etiology or unifying sequence of molecular events for the most common form of PD, late onset sporadic idiopathic PD, has not been established. Because a growing number of epidemiological studies have associated an increased risk for PD with various conditions, environmental factors must be considered as a risk for PD. The goal of our research is to identify mechanisms of environmental agents that contribute to increased risk for PD. We are currently investigating whether four classes of pesticides, that have established human exposure, can impair ubiquitin based protein processing and cell signaling that promotes neurodegenerative changes contributing to PD. Animal models are being used to determine whether these pesticides inhibit E1 activating enzyme through a common mechanism in vivo leading to nigrostriatal and extra nigral toxicity. These studies are determining the dose-response for changes in brain E1 enzyme activity, characterizing E1 covalent modifications by shotgun LC/MS/MS, mapping neurodegenerative changes both in the nigral striatal pathway and in potentially more sensitive nonmotor brain regions and enteric ganglia involved in PD using immunohistochemistry and silver degeneration staining. In vitro systems are being used to ascertain the cause and effect relationship for ubiquitin pathway inhibition and dopaminergic cell death through determining the influence of constitutively compromised and increased E1 function on viability and the localization and expression of the dopamine transporter and activation of the Cdk5 complex in differentiated MN9D cells exposed to either the proposed pesticides, their metabolites or specific pharmacologic E1 inhibitors. We believe that the mechanistic data and structure activity relationships derived from these studies will assist in the formulation of more informed risk management for the large population exposed to these agents and will facilitate strategies of intervention to decrease the risk of PD and slow the progression of disease in PD patients.