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The Morris K. Udall Center of Excellence for Parkinson’s Disease Research at the Johns Hopkins University School of Medicine


Director: Ted M. Dawson, M.D., Ph.D.

Website: http://www.hopkinsmedicine.org/neurology_neurosurgery/research/udall_center/

Budget End Date: 7/31/2019

Central Theme

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.

Center Structure

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:

  • Biology of Parkin and Its Role in Parkinson’s Disease (Dr. Ted M. Dawson)
  • Understanding Mechanisms of α-synuclein pathology (Dr. Han Seok Ko)
  • Establishing clinical utility of CSF biomarkers for PD (Dr. Akhilesh Pandey)
  • LRRK2 Biology in Parkinson’s Disease (Dr. Valina L. Dawson)

And four Cores:

  • Administrative and Training (Dr. Ted M. Dawson)
  • Clinical (Dr. Liana Rosenthal)
  • Neuropathology (Dr. Juan C. Troncoso)
  • Proteomics (Dr. Akhilesh Pandey)

Recent Significant Advances

  • Neurobiology of PD
    • Discovery of the enzymatic function of parkin, DJ-1 and LRRK2
    • Identification of LRRK2 phosphosubstrates
    • Discovery of PARIS (parkin interacting substrate)
    • Discovery that the cell death mechanism, Parthanatos, plays an important role in the degeneration of dopamine neurons in PD
  • PD Model Systems
    • Generation of animal and cellular models of the genetic causes of PD.
    • Generation of adult conditional knockouts of parkin creating the first accurate model of neurodegeneration in PD
    • Discovery the adult conditional knockout of parkin leads to mitochondrial biogenesis defects in dopamine neurons
  • Target identification
    • Identification of novel targets to slow the progression of PD by discovering the molecular mechanisms by which genetic mutations cause PD

Resources Available

  • Animal Models
    • Parkin Knockouts (Germline and Conditional)
    • DJ-1 Knockouts
    • Alpha-Synuclein Transgenics
    • LRRK2 Knockouts
    • LRRK2 Transgenics
    • AIMP2 Transgenics
  • iPSC models of PD
  • Stable Cell Culture Models
  • Viral Expression Systems
  • Expression constructs for most PD related genes
  • Antibody production
  • Human postmortem PD and related disorder brains

Plans for the Coming Year

  • To understand the interrelationship between familial and sporadic PD through the investigation of the shared cellular pathways between parkin, the most common cause of autosomal recessive PD, a-synuclein, which is causal in sporadic PD and LRRK2, the most common cause of autosomal dominant PD.
  • To investigate cell signaling and pathways using gold standard molecular, transgenic, neuropathologic, cell biologic and neurobehavioral approaches as well as emerging cutting edge advanced technologies in mRNA translation, transcriptome and proteome analysis.
  • To identify master regulators of neurodegeneration in PD and to identify useful biomarkers for PD and progression of PD

Center Goals aligned with NINDS PD2014 Research Priorities:

The Johns Hopkins Udall Center addresses several NINDS PD2014 research priorities, including:

  • Clinical Research Recommendation 4: Develop biomarkers of target engagement and proximal pharmacodynamic effects for use in early-stage clinical trials 
  • Translational Research Recommendation 8: Develop a thorough understanding of targets and pathways associated with pathogenesis and pathophysiologic mechanisms of PD with emphasis on those validated by human genetics and biology.
  • Translational Research Recommendation 9: Investigate the relationship between converging pathways in PD, for example α- synuclein misfolding and mitochondrial function
  • Basic Research Recommendation 2: Elucidate the normal and abnormal function of a-synuclein and its relationship to other PD genes
  • Basic Research Recommendation 4: Generate and characterize PD-specific iPS cells (sporadic and genetic, including isogenic lines) for “omic” (transcriptomics, proteomics) pathway analysis. 
  • Basic Research Recommendation 8:  develop a more detailed understanding of the molecular determinants and mechanisms of a-synuclein aggregation.

Select Recent Publications

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].

Additional Accomplishments

  • Integration with other Udall Centers: Since its inception the Johns Hopkins Udall Center has shared expertise, tools, reagents, clinical data and biospecimens with other Udall Centers including the Mayo Clinic Jacksonville, the University of Pennsylvania and the University of Washington.  Our biomarker discovery and validation efforts proposed in Project 3 would not be possible without participation in the Udall Center Network since it is only through participation that we have sufficient sample size and statistical power to make definitive conclusions. 

  • Center Outreach Activities: The Johns Hopkins Udall Center recognizes that lay and professional outreach and education are an integral component of a comprehensive plan to serve the regional Parkinson’s community including Maryland, Washington D.C., Virginia, West Virginia, Delaware, and South Central Pennsylvania.  Consequently, we have developed informal advisory and collaborative relationships with regional support groups and non-profit organizations such as the Parkinson Foundation of the National Capitol Area; the Delmarva Parkinson’s Alliance; the Maryland Association for Parkinson Support; the Parkinson Education and Support group of Sussex County Delaware; the Hagerstown Support Group; the Lancaster County Support Group; and the Martinsburg, West Virginia Support Group.  We have also worked closely with national groups including Cure PSP, the Parkinson Action Network, the Parkinson Foundation, the National Parkinson Foundation, and the Michael J. Fox Foundation.  These relationships have allowed us to leverage our resources to best serve the Parkinson’s community. The outreach and education programs resulting from these collaborative efforts have focused on lay programs as well as professional education for all persons, including those in rural and urban underserved areas. 

 

Public Health Statement

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