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The overall goals of the Johns Hopkins University School of Medicine' Morris K. Udall Parkinson's Disease Research Center of Excellence are: (1) to study and characterize parkin, proteins that interact with parkin, and other proteins that may play important roles in the pathogenesis of Parkinson’s disease (PD) using cellular models, transgenic mice, and human postmortem material from PD patients, patients with parkinsonism, and aged-matched controls; (2) to explore the role of alpha-synuclein in PD and related synucleinopathies by characterizing cellular and transgenic models of alpha-synuclein-induced neurodegeneration; (3) to explore the role of DJ-1 in PD; (4) to define the importance of the interactions among alpha-synuclein, synphilin-1, DJ-1, and parkin in the pathogenesis of PD and related synucleinopathies through studying cellular models, transgenic mice, and human postmortem tissue; and (5) to determine whether alpha-synuclein metabolism, processing, and post-translational modifications play important roles in the pathogenesis of PD and human alpha-synucleinopathies.

The Program represents a multidisciplinary, mechanistic approach involving interactive, productive investigators with complementary areas of expertise who have long been committed to studies of neurodegenerative diseases. One major aim will be to integrate the activities of the various disciplines so that the interrelationships will result in a greater scientific contribution than could be achieved if each Project were pursued individually.

The Program consists of four Projects: (1) Mouse Models of Parkin Biology and Pathobiology, (2) PD Cell Models ― Alpha-Synuclein and Interacting Proteins, (3) Mechanisms of Neurodegeneration in Human Alpha-Synuclein Transgenic Mice, and (4) the Role of DJ-1 in PD; and four Cores, (A) Administrative and Training; (B) Transgenic and Neurobehavior; (C) Neuropathology, and (D) Clinical.

The Program has one major theme, to understand the role of the familial-associated genes alpha-synuclein, parkin, and DJ-1 in the pathogenesis of PD and related disorders. The role of alpha-synuclein, parkin, DJ-1, and synphilin-1 in PD pathogenesis is being investigated using molecular, transgenic, neuropathologic, cell biologic, and neurobehavioral approaches to examine the mechanism of neuronal dysfunction and injury due to alterations in these gene products. The mechanism of neuronal loss in Parkin knockout mice and alpha-synuclein A53T transgenic mice is being characterized. We are determining whether parkin interacts with alpha-synuclein and further investigating the relationship between and parkin, alpha-synuclein, and synphilin-1. We are exploring the importance of parkin-mediated ubiquitination and the role of K-48 versus K-63 ubiquitin linkages. Transgenic animal models of familial PD and human alpha-synucleinopathies overexpressing human wild-type alpha-synuclein, the A53T and A30P mutations of alpha-synuclein, are being studied and characterized. We also are exploring alpha-synuclein processing and modifications and the relationship of synphilin-1 to alpha-synuclein. Furthermore, we are investigating the potential function of DJ-1 and its role in PD pathogenesis. We believe that our multidisciplinary approach has the capacity to produce unique information concerning the mechanisms of neuronal injury in genetic animal models of PD and the related synucleinopathies, and to lead to better understanding of the function and the role of alpha-synuclein, parkin, DJ-1, and synphilin-1 in normal and pathophysiologic processes related to PD.

Contact Information or Related Web Links:

Ted Dawson, M.D., Ph.D.
Leonard and Madlyn Abramson Professor of Neurodegenerative Diseases
Institute for Cell Engineering
733 North Broadway Street, suite 731
Johns Hopkins University School of Medicine
Phone: (410) 614-3359
Fax: (410) 614-9568
Email: tdawson@jhmi.edu

The Parkinson's Disease Movement Disorders Center

Last updated February 09, 2005