Director: Ted M. Dawson, M.D., Ph.D.
Budget End Date: 7/31/2019
The initial description of Parkinson’s Disease (PD) was based on six cases reported by James Parkinson in 1817. Over the last 197 years the etiology of the disease still remains poorly understood. The social and financial costs of PD are formidable with a recent estimate of the cost of medications alone world-wide to be $11 billion. It is estimated that PD affects more than 630,000 individual in the United States; and the total annual costs in the United States in 2010 were estimated to be $14.4 billion. The disease is relentlessly progressive and despite effective symptomatic therapy in the early stages of the illness most patients have substantial morbidity and disability. Due to the significant impact on the quality of patients’ lives and their families as well the enormous economic consequences of PD there is an urgent need to understand the etiology and pathogenesis of PD so that more effective symptomatic therapies and ultimately preventive therapies can be developed. One of the major goals of the Johns Hopkins Udall Center is to understand the interrelationship between parkin, the most common cause of autosomal recessive PD (Project 1), a-synuclein, which is causal in sporadic PD (Project 2) and LRRK2, the most common cause of autosomal dominant PD (Project 4) and to use our discoveries to develop disease and progression markers (Project 3) and ultimately new therapies. The insights into how these three genes interact in the pathogenesis of PD and the discovery of biomarkers would not be possible without the Udall Center structure as it enables the evaluation of these major causes of PD and the ability to evaluate findings in each arm of PD to elucidate common pathways if they exist as these may provide the best opportunities for comprehensive new therapies and biomarkers. We believe that our multi-disciplinary approach has the capacity to produce unique information concerning the mechanisms of neuronal injury in animal models of PD that will lead to a better understanding of the function and the role of a-synuclein, parkin, and LRRK2 in normal and pathophysiologic processes related to PD.
The program represents a multi-disciplinary, 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:
And four Cores:
The Johns Hopkins Udall Center addresses several NINDS PD2014 research priorities, including:
Stevens, D.A., Y. Lee, H.C. Kang, B.D. Lee, Y.I. Lee, A. Bower, H. Jiang, S.A. Andrabi, V.L. Dawson, J.-H. Shin and T.M. Dawson “Parkin Loss Leads to PARIS-Dependent Declines in Mitochondrial Mass and Respiration,” Proc. Natl. Acad. Sci, 2015, 113:11696-701.PMCID: PMC4577198 [Available on 2016-03-15].
Srivatsal, S., B. Cholerton, J.B. Leverenz, Z.K. Wszolek, R.J. Uitti, D. Weintraub, J.Q. Trojanowski, V.M. Van Deerlin, J.F. Quinn, K.A. Chung, A.L. Peterson, S.A. Factor, C. Wood-Siverio, J.G. Goldman, G.T. Stebbins, B. Bernard, B. Ritz, R. Rausch, A.J. Espay, F.J. Revilla, J. Devoto, L.S. Rosenthal, T.M. Dawson M.S. Albert, I.F. Mata, S.-C. Hu, K.S. Montine, C. Johnson, T.J. Montine, K.L. Edwards, C.P. Zabetian “Cognitive Profile of LRRK2-related Parkinson’s Disease.” Mov Disord, 2015, Apr 15;30(5):728-33. PMCID: PMC4397146 [Available on 2016-04-15].
Beecham G. W., D.W. Dickson, W.K. Scott, E.R. Martin, G. Schellenberg, G., Alzheimer Disease Genetics Consortium, K. Nuytemans, E.B. Larson, J.D. Buxbaum, J.Q. Trojanowski, V.M. Van Deerlin, H.I. Hurtig, D. C. Mash, T.G. Beach, J.C. Troncoso, O. Pletnikova, M.P. Frosch, B. Ghetti, T.M. Foroud, L.S. Honig, K. Marder, J.P. Vonsattel, S.M. Goldman, H.V. Vinters, O.A. Ross, Z.K. Wszolek, L. Wang, D.M. Dykxhoorn, M.A. Pericak-Vance, T.J. Montine, J.B. Leverenz, T.M. Dawson, J.M. Vance. “The PARK 10 locus is a major locus for sporadic, neuropathologically-confirmed Parkinson disease.” Neurology, 2015, 84:972–980. PMCID: PMC4352096 [Available on 2016-03-10].
Tremendous advances in understanding the pathogenesis of a variety of neurodegenerative disorders have been made by the study of genes implicated in familial degenerative disorders such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), familial prion disorders and triple repeat (CAG) disorders such as Huntington’s disease. Mutations in the amyloid precursor protein and presenilins are responsible for some early onset cases of familial AD, mutations in the superoxide dismutase type-1 (SOD1) gene have been implicated in a subset of cases of familial ALS, mutations in the prion protein gene cause several familial prion disorders and CAG-expanded repeats in different genes cause Huntington’s disease, DRPLA, and some of the spinal cerebellar atrophies. Most importantly for this proposal, mutations in alpha-synuclein, parkin and LRRK2 have been linked to familial PD. The JHMI Morris K. Udall Center has chosen to focus on the most common autosomal recessive (parkin) and autosomal dominant PD (LRRK2) linked genes and alpha-synuclein due to its potential role in both sporadic and familial PD. It is our tenet that understanding the molecular mechanisms by which mutations in these three genes and their relationship to the more common sporadic form of PD has the greatest potential to enhance our understanding of pathogenic mechanisms in PD. Along these lines, Project 1, focuses on in vitro and in vivo models of parkin biology and Projects 2 focuses on in vitro and in vivo models, of alpha-synuclein biology and Project 4 focuses on in vitro and in vivo models LRRK2 biology and Project 3 focuses on developing biomarkers that emerge from investigations in Projects 1, 2, and 4. This multi-disciplinary approach has the capacity to produce unique information concerning the mechanisms of neuronal injury in murine and human models of PD and the related synucleinopathies and to lead to better understanding of the function and the role of a-synuclein, parkin, and LRRK2 in normal and pathophysiologic processes related to PD.
Last Modified February 9, 2016