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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.hopkinspd.com

Central Theme

To understand the role of familial associated genes alpha-synuclein, parkin and LRRK2 in the pathogenesis of Parkinson’s disease and related disorders.  Molecular, transgenic, neuropathologic, cell biologic and neurobehavioral approaches will be used to investigate the roles of alpha-synuclein, parkin, and LRRK2 in PD pathogenesis as well as to examine the mechanism of neuronal dysfunction and injury due to alterations in these gene products.  The mechanism of neuronal loss in LRRK2 transgenic mice and alpha-synuclein A53T transgenic mice will be characterized. We will explore the relationship between parkin, alpha-synuclein and oxidative and nitrosative induced inactivation of parkin. We will explore the importance of the parkin substrate AIMP2 in the pathogenesis of PD due to parkin inactivation. Transgenic and cellular models of AIMP2 will be studied and characterized. Transgenic animal models of familial PD and human alpha-synucleinopathies over expressing human wild type alpha-synuclein, the A53T and E46K mutations of alpha-synuclein, will be further studied and characterized with a particular emphasis on oxidative and nitrosative stress and mitochondrial dysfunction.  Transgenic and cellular models of LRRK2 will be studied and characterized.  We will explore and identify LRRK2 phosphosubstrates and their potential role in the pathogenesis of PD. We believe that our multi-disciplinary approach has the capacity to produce unique information concerning the mechanisms of neuronal injury in genetic animal models of PD and the related synucleinopathies, which will lead to better understanding of the function and the role of alpha-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 three Projects:

  • Biology of Parkin and Its Role in Parkinson’s Disease (Ted M. Dawson)
  • Mechanisms of Neurodegeneration in Alpha-Synuclein Transgenic Mice (Han Seok Ko)
  • LRRK2 Biology in Parkinson’s Disease (Valina L. Dawson)

And four Cores:

  • Administrative and Training (Ted M. Dawson)
  • Bioenergetics (Valina L. Dawson)
  • Transgenic and Neurobehavior (Ted M. Dawson)
  • Clinical and Neuropathology (Susan Bassett and Juan C. Troncoso)

Recent Significant Advances

  • Discovery of the enzymatic function of parkin, DJ-1 and LRRK2
  • 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
  • Identification of novel targets to slow the progression of PD by targeting the molecular mechanisms by which genetic mutations cause PD
  • Discovery of PARIS

Resources Available

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

Plans for the Coming Year

The overall goals of this proposal are to:

  1. To study and characterize parkin, proteins that interact with parkin, and the impact of oxidative and nitrosative stress on parkin 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 LRRK2 in PD.
  4. To define the importance of the interactions among oxidative and nitrosative stress, alpha-synuclein, parkin and LRRK2 in the pathogenesis of PD and related synucleinopathies through studying cellular models, transgenic mice and human postmortem tissue.
  5. To determine how oxidative and nitrosative stress leads to inactivation of parkin and how this contributes to the pathogenesis of PD.  

Select Recent Publications

  1. Ramonet, D., J.P. Daher,  B.M. Lin, K. Stafa, J. Kim, R. Banerjee, M. Westerlund, O. Pletnikova, L. Glauser, L. Yang, Y. Liu, D.A. Swing, M.F. Beal, J.C. Troncoso, J.M. McCaffery, N.A. Jenkins, N.G. Copeland, D. Galter, B. Thomas, M.K. Lee, T.M. Dawson, V.L. Dawson, D.J. Moore. “Dopaminergic Neuronal Loss, Reduced Neurite Complexity and Autophagic Abnormalities in Transgenic Mice Expressing G2019S Mutant LRRK2.” PLoS ONE 6(4): e18568. doi:10.1371/journal.pone.0018568  PMID: 21494637  (2011)
  2. Harraz, M.M., T.M. Dawson and V.L. Dawson., “MicroRNAs in Parkinson’s Disease.” J. Chem Neuroanatomy, 42:127-130 (2011) PMID: 21295133
  3. Martin, I., V.L. Dawson and T.M. Dawson, “Recent Advances in the Genetics of Parkinson’s Disease.” Annual Review of Genomics and Human Genetics, 12:301-325 (2011) PMID: 21639795
  4. Dawson, T.M. and V.L. Dawson. “A lysosomal lair for two pathogenic proteins.”  Science Translational Medicine, 2011 Jul 13;3(91):91ps28 (2011) PMID: 21753118
  5. Liu, Z., S. Hamamichi, B.D Lee, D. Yang, G.A. Caldwell, K.A. Caldwell, T.M. Dawson, W.W. Smith, V.L. Dawson. “ Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in C. elegans and Drosophila Parkinson’s Disease Models., Human Molecular Genetics, 20:3933-42 (2011) PMID: 21768216
  6. Chew, K.C., E.T. Ang, Y.K. Tai, F. Tsang, S.Q. Lo, E. Ong, W.Y. Ong, H.M. Shen, K.L. Lim, V.L. Dawson, T.M. Dawson and T.W. Soong. “Enhanced autophagy from chronic toxicity of iron and mutant A53T -synuclein: Implications for neuronal cell death in Parkinson’s disease.” Journal of Biological Chemistry, 286:33380-33389 (2011) PMID: 21795716
  7. Ramsden, N., J. Perrin, Z. Ren, B.D. Lee, N. Zinn, V.L. Dawson, D. Tam, M. Bova, M. Delling, G. Drewes, M. Bantscheff, F. Bard, T. M. Dawson, C. Hopf. “Chemoproteomics-based design of potent LRRK2-selective chemical probes that attenuate Parkinson’s disease-related toxicity in human neurons.” ACS Chemical Biology, 6:1021-1028 (2011). PMID: 21812418
  8. Xu, J.-C. and T.M. Dawson. “A Perfect ‘‘Match’’ for In Vitro Human Disease Modeling and Autologous Cell-Based Transplantation Therapy: Generating Genetically Identical Parkinson’s Disease and Control Pluripotent Stem Cells by Precise Gene Targeting.” Movement Disorders, 26: 1804 (2011)
  9. Nikonova, E.V., Y. Xiong, K.Q. Tanis, V.L. Dawson, R.L. Vogel, D.J. Stone, I.J. Reynolds, J.T. Kern and T.M. Dawson. “Transcriptional Responses to Loss or Gain of Function of the Leucine-Rich Repeat Kinase-2 (LRRK2) Gene Uncover Biological Processes Modulated by LRRK2 Activity. Human Molecular Genetics, 21:163-174 (2012) Epub 2011 Oct 4, PMID:21972245
  10. Lee, B.D., X. Li, T.M. Dawson, and V. L. Dawson.  “Measuring the activity of Leucine Rich Repeat Kinase 2 (LRRK2) – a kinase involved in Parkinson’s disease.” Methods in Molecular Biology, 795:45-54 (2012). PMID: 21960214
  11. Galluzzi, L., I. Vitale, J.M. Abrams, E.S. Alnemri, E.H. Baehrecke, M.V. Blagosklonny, T.M. Dawson, V.L. Dawson, W.S. El-Deiry, S. Fulda, E. Gottlieb, D.R. Green, M.O. Hengartner, O. Kepp, R.A. Knight, S. Kumar, S.A. Lipton, F. Madeo, W. Malorni, P. Mehlen, G. Nuñez, M.E. Peter, M. Piacentini, D.C. Rubinsztein, H.-U. Simon, P. Vandenabeele, E. White, J. Yuan, B. Zhivotovsky, G. Melino and G. Kroemer. “Molecular definitions of cell death subroutines: Recommendations of the Nomenclature Committee on Cell Death 2012.” Cell Death and Differentiation, 19:107-20 (2012) PMID: 21760595
  12. Pankratz, N., G.W. Beecham, A.L. DeStefano, T.M. Dawson, K.F. Doheny, S.A. Factor, T.H. Hamza, A.Y. Hung, B.T. Hyman, A.J. Ivinson, D. Krainc, J.C. Latourelle, L.N. Clark, K. Marder, E.R. Martin, R. Mayeux, O.A. Ross, C.R. Scherzer, D.K. Simon, C. Tanner, J.M. Vance, Z.K. Wszolek, C.P. Zabetian, R.H. Myers, H. Payami, W.K. Scott, T. Foroud, and the PD GWAS Consortium., “Meta-analysis of Parkinson disease: Identification of a novel locus, RIT2” Annals of Neurology, 71:370–384 (2012) PMID: 22451204
  13. Xiong, Y., C. Yuan, R. Chen, T.M. Dawson* and V.L. Dawson*, “ArfGAP1 is a GTPase Activating Protein for LRRK2: Reciprocal Regulation of ArfGAP1 by LRRK2.  Journal of Neuroscience, 32:3877-3886 (2012). *Co-corresponding and senior authors
  14. Stankowski, J.N. V.L. Dawson and T.M. Dawson, “Ironing out Tau’s Role in Parkinson’s Disease.” Nature Medicine, 18:197-8 (2012). PMID:22310680
  15. Lee, B.D., V.L. Dawson, T.M. Dawson, “Leucine rich repeat kinase 2 (LRRK2) as a potential therapeutic target for Parkinson’s Disease,” Trends in Pharmacological Sciences, 33:365-373 (2012). PMID:22578536
  16. Daher, J.-P.L. O. Pletnikova, S. Biskup, A. Musso, J.C. Troncoso, S. Gellhaar, D. Galter, M.K. Lee, T.M. Dawson, V.L. Dawson and D.J. Moore, “Neurodegenerative phenotypes in an A53T -synuclein transgenic mouse model are independent of LRRK2.” Human Molecular Genetics, 21:2420-31 (2102). PMID: 22357653
  17. Cooper, O., H. Seo, S. Andrabi, C. Guardia-Laguarta, J. Graziotto, M. Sundberg, J.R. McLean, L. Carrillo-Reid, Z. Xie, T. Osborn, G. Hargus, M. Deleidi, T. Lawson, H. Bogetofte, E. Perez-Torres, L. Clark, C. Moskowitz, J. Mazzulli, L. Chen, L. Volpicelli-Daley, N. Romero, H. Jiang, R.J. Uitti, Z. Huang, G. Opala, L.A. Scarffe, V.L. Dawson, C. Klein, J. Feng, O.A. Ross, J.Q. Trojanowski, V.M.-Y. Lee, K. Marder, D.J. Surmeier, Z.K. Wszolek, S. Przedborski1, D. Krainc, T.M. Dawson, O. Isacson. “Familial Parkinson’s disease iPSCs show cellular deficits in mitochondrial responses that can be pharmacologically rescued.” Science Translational Medicine 4, 141ra90 (2012); DOI: 10.1126/scitranslmed.3003985
  18. Lee, Y., V.L. Dawson and T.M. Dawson, “Animal models of PD: Vertebrate genetic.” Parkinson’s Disease, ed. S. Przedborski, Cold Spring Harbor Press, in press (2012)
  19. Calabresi, P., M. DiFilippo, A. Gallina, Y. Wang, J.N. Stankowski, B. Picconi, V.L. Dawson, T.M. Dawson. “New synaptic and molecular targets for neuroprotection in Parkinson’s disease.” Movement Disorders, in press (2012)
  20. Giovinazzo, D., V.L. Dawson, T.M. Dawson. “Nitric Oxide” Encyclopedia of Neurological Sciences eds. M. J. Aminoff and R.B. Daroff, Academic Press, 2nd edition, in press (2012)
  21. Xiong, Y., V.L. Dawson, T.M. Dawson. “LRRK2 GTPase Dysfunction in the Pathogenesis of Parkinson’s Disease.  “Biochemical Society Transactions,” in press (2012)
  22. Colla E, Jensen PH, Pletnikova O, Troncoso JC, Glabe C, Lee MK. “Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo.” J Neurosci. 2012 Mar 7;32(10):3301-5
  23. Ramonet D, Podhajska A, Stafa K, Sonnay S, Trancikova A, Tsika E, Pletnikova O, Troncoso JC, Glauser L, Moore DJ. “PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity.” Hum Mol Genet. 2012 Apr 15;21(8):1725-43
  24. Pontone GM,  Palanci J, Williams JR, Bassett SS. Screening for DSM-IV-TR Cognitive Disorder NOS in Parkinson's disease using the Mattis Dementia Rating Scale, International Journal of Geriatric Psychiatry, in press)
  25. Mack J, Rabins P, Anderson K, et al. Prevalence of psychotic symptoms inn a community-based Parkinson disease sample. Am J Geriatr Psychiatry. 2012 20(2)123-32.Almer et al., Ocular motor and sensory function in Parkinson’s disease. Ophthalmology. 2012, 119(1):178-82
  26. Pontone GM, Williams JR, Anderson K, et al., Anxiety and self-perceived health status in Parkinson’s disease. Parkinsonism & Related Disorders; 2011. May;17(4):249-54
  27. Pontone GM, Palanci J, Bienvenu O, et al., Familial aggregation of panic disturbances in Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 2011. 23(4):417-24
  28. Palanci J, Marsh l, Pontone GM. Gaps in treatment for anxiety in Parkinson’s disease.  Am J Geriatr Psychiatry 2011. 19(10)907-8

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, will focus on in vitro and in vivo models of parkin biology and Projects 2 will focus on in vitro and in vivo models, of alpha-synuclein biology and Project 3 will focus on in vitro and in vivo models LRRK2 biology.  

Outreach Activities

Our Center recognizes that research endeavors are complimented by lay and professional educational and outreach programs that serve the international and regional Parkinson’s disease community.  The regional community includes Maryland, Washington DC, Virginia, West Virginia, Delaware, and South Central Pennsylvania.  The international community includes all of those living with PD who routinely visit, phone or email our Center for care, information, and guidance.  We have developed informal advisory and consultative relationships with the regional support groups and non-profit organizations such as the Parkinson Foundation of the National Capital Area, Cure PSP, the Delmarva Parkinson’s Alliance, the Lancaster County Parkinson’s Support Group, the Baltimore Health Disparities Coalition, and the Berkely County West Virginia Support Group.  We have been able to locate the underserved and unserved individuals and families living with this complex disease within rural and urban areas by working collaboratively with the previously mentioned organizations and others.  We continue to sponsor local symposia in our area and participation has grown to 450 participants annually as a result of collaboration with PFNCA and the local academic institutions. These successes are the result of collaboration, which allows us to leverage professional and financial resources.

Dr. Ray Dorsey has led the expansion of our telemedicine efforts to provide care to individuals directly in their communities and even their homes.  National Public Radio recently highlighted this novel, patient-centered effort. We have expanded our telemedicine efforts internationally and have now cared for patients in six countries on three continents.  The symposium success has provided the groundwork for a telemedicine initiative in the Delmarva area, expanding the outreach of clinical care to this rural area.  This significant outreach activity has resulted in a demand for the remote services of a Movement Disorder physician.  There are no such physicians on the Delmarva Peninsula.  By improving access to specialty neurologists, we hope to improve the quality of care available all patients living with PD.  

Support group leader training is offered at least annually.  The training has spurred the initiation or revitalization of about 4-6 support groups each year.  Faculty and staff provide about 120 speaking engagements each year to support groups and professional groups.  

Educational initiatives which focus on professional education include the Edmund Safra Foundation Nurse Faculty Training in Parkinson’s Disease, outreach to Area Health Education Centers, the provision of multiple training programs to local nursing homes,  participation in the American Physical Therapy Association’s annual conference,  and  the mentoring of several students from area universities including local institutions serving a largely minority population.  The Delaware Division of Medicaid and Medical Assistance annual Nursing Conference had 45 participants comprised of registered nurses.  The topic of the program was Parkinson’s and Movement Disorders.  The May 2011 Edmund Safra Foundation program trained six local nursing faculty members.  Arita McCoy one of our research nurses was able to audit the program.  

Our center’s outreach and education mission is committed to serving the entire Parkinson’s community, which includes those living with the disease and their families.  We estimate that 1250 individuals with PD and their families have participated in the educational programs and up to 100 professionals have benefited from the professional educational efforts.  All programs are targeted to reach the lay and professional community, which ultimately supports the Center’s robust research efforts and the patients and families, which we are privileged to serve.

Last updated March 20, 2013