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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/

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 the disease 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), α-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 α-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 (Ted M. Dawson, MD, PhD)
  • Understanding Mechanisms of α-synuclein pathology (Han Seok Ko, PhD)
  • Establishing clinical utility of CSF biomarkers for PD (Akhilesh Pandey, MD, PhD)
  • LRRK2 Biology in Parkinson’s Disease (Valina L. Dawson, PhD)

And four Cores:

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

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
  • Identification of LRRK2 phosphosubstrates
  • Discovery of PARIS
  • Discovery that Parthanatos plays an important role in the degeneration of dopamine neurons in PD
  • Description of the first draft of the human proteome

Resources Available

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

Plans for the Coming Year

  1. 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, α-synuclein, which is causal in sporadic PD and LRRK2, the most common cause of autosomal dominant PD.
  2. Cell signaling and pathways will be investigated 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.
  3. The goal is to identify master regulators of neurodegeneration in PD and to identify useful biomarkers for PD and progression of PD
  4. We believe that our 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 α-synuclein, parkin, and LRRK2 in normal and pathophysiologic processes related to PD.

Relationship of Center Goals to the NINDS PD2014 Recommendations:

The Johns Hopkins Udall Center addresses 13 of the NINDS PD2014 Research Recommendations:

  1. Basic Research Recommendation (BRR) 1 – development and characterization of transmission models of pathologic α-synuclein (Projects 1, 2 & 4)
  2. BRR 2 – elucidating the normal and abnormal function of α-synuclein and its relationship to other PD genes (parkin – Project 1 & 2), (LRRK2 – Projects 2 & 4).
  3. BRR 3 – understanding how different cell populations change in their coding properties and how these changes relate to behavior and motor control (Project 4).
  4. BRR 4 – generating and characterizing PD-specific iPS cells (sporadic and genetic, including isogenic lines) for “omic” (transcriptomics, proteomics) pathway analysis (Project 4).
  5. BRR 5 - integration of comprehensive datasets coupled with functional analyses (Projects 1, 2, 4 and Proteomic Core D).
  6. BRR 8 – developing a more detailed understanding of the molecular determinants and mechanisms of α-synuclein aggregation (Project 2).
  7. BRR 7 – developing a more detailed understanding of the genetic basis of PD (Clinical Core C & Neuropathology Core D).
  8. BRR 11 – advance our understanding of neural circuits, circuit analysis techniques (Projects 1, 2, 4 & Neuropathology Core C).
  9. Translational Research Recommendation (TRR) 8 in which the entire Johns Hopkins Udall Center is focused on developing a through understanding of targets and pathways associated with pathogenesis and pathophysiologic mechanisms of PD with an emphasis on those validated by human genetics and biology.
  10. TRR 9 - investigating the relationship between converging pathways in PD (All Projects and Cores).
  11. Clinical Research Recommendation (CRR) 1 – defining the features and natural history of prodromal PD including progression … and biomarkers (Clinical Core B, Neuropathology Core C and Project 3).
  12. CRR 3 – characterizing the long-term progression of PD… include… biological factors such as genotype and biomarkers (Clinical Core B, Neuropathology Core C and Project 3).
  13. CRR 4 – developing biomarkers of target engagement and proximal pharmacodynamic effects for use in early-stage clinical trials (Clinical Core B, Neuropathology Core C and Project 3).

Select Recent Publications

  1.  Stafa, K., E. Tsika, R. Moser, A. Musso, L. Glauser, A. Jones, S. Biskup, Y. Xiong, R. Bandopadhyay, V.L. Dawson, T.M. Dawson, D.J. Moore. “Functional interaction of Parkinson's disease-associated LRRK2 with members of the dynamin GTPase superfamily” Hum Mol Genet. 23:2055-2077 (2014). PMCID: PMC3959816.
  2. Lee, Y-I , D. Giovinazzo, H.C. Kang, Y. Lee, J.S. Jeong, P-T Doulias, Z. Xie, J. Hu, M. Ghasemi, H. Ischiropoulos, J. Qian, H. Zhu, S. Blackshaw, V.L. Dawson, T.M. Dawson. “Protein Microarray Characterization of the S-Nitrosoproteome.” (EPub Oct 2013) Mol. Cell. Proteomics 13(1):63-72 (2014). PMCID: PMC3879630.
  3. Nuytemans, K., V. Inchausti, G.W. Beecham, L. Wang, D.W. Dickson, J.Q. Trojanowski, V.M.-Y. Lee, D.C. Mash, M.P. Frosch, T. Foroud, L.S. Honig, T.J. Montine, T.M. Dawson, E.R. Martin, W.K. Scott, J.M. Vance. “Absence of C9ORF72 expanded or intermediate repeats in autopsy confirmed Parkinson Disease.” Movement Disorders, (2014) Feb 26. doi: 10.1002/mds.25838. [Epub ahead of print]. PMCID: PMC4022044.
  4. Martin, I., J.W. Kim, B.D Lee, H.C. Kang, J.-C. Xu., H. Jia, J. Stankowski, M.-S. Kim, J. Zhong, M. Kumar, S. Andrabi, A Pandey, T.M. Dawson*, V.L. Dawson*. “Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson’s disease” Cell, 157:472-485 (2014). PMCID: PMC4040530. *Co-corresponding and senior authors.
  5. Karuppagounder, S.S., S. Brahmachari, Y. Lee, V.L. Dawson, T.M. Dawson and H.S. Ko. “The c-Abl Inhibitor, Nilotinib, Protects Dopaminergic Neurons in a Preclinical Animal Animal Model of Parkinson’s disease.” Science Reports, 4, 4874; DOI:10.1038/srep04874 (2014). PMCID: PMC4007078.

Other Accomplishments

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. Our Center interacts with all 45 – 50 of the regional support groups offering regular support group leader networking opportunities. Center professionals provide guidance to new group leaders resulting in the creation of about two to three groups per year. We facilitate eight groups on a monthly basis. Center faculty and staff routinely provide over 100 speaking engagements on topics such as research updates, self-management, and the basics of Parkinson’s disease. We have been instrumental in the provision of annual symposia locally and in such rural locations as Lewes, Delaware; Lancaster, Pennsylvania; and Martinsburg, West Virginia. Well over 300 individuals attend these symposia. A total of over 150 attend the regular education programs including: PD 101, PD 201, Caregiver Education workshops, and the DBS seminar annually. A key element to the success of these programs is our newsletter, which is mailed to over 2000 individuals twice yearly. Another contributor to success is the networking by Center staff during health fairs and within the Area Agencies on Aging, the Maryland Gerontological Society, the Baltimore and Harford County Provider Counsels, the Johns Hopkins Geriatrics Center, and during Area Health Education Center events. All of these activities engage the community so that we can disseminate current knowledge and provide updates on research. Highlights of professional outreach and education programs include the following: hosting the Edmond J. Safra Foundation’s Visiting Nurse Faculty Training in Parkinson’s for five years; participation in the Baltimore Health Disparities Coalition, development and creation of several CEU programs for nursing professionals, physical therapists, and allied team members; and collaboration with the Johns Hopkins School of Nursing to create and provide curriculum on Parkinson’s for the Johns Hopkins Guided Care Nursing Program.

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.

Last updated October 1, 2014