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/Udall_Center.html

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. The role of alpha-synuclein, parkin, and LRRK2 in PD pathogenesis will be 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 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 and to 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.
• Identification of novel targets to slow the progression of PD by targeting the molecular mechanisms by which genetic mutations cause PD

Available Resources

• Animal Models
  • Parkin Knockouts
  • 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

Ko, H.S. R. Bailey, W.W. Smith, A. Liu, J.-H. Shin, Y.-I. Lee, Y.-J. Zhang, H. Jiang, C.A. Ross, D.J. Moore, C. Patterson, L. Petrucelli, T.M. Dawson*, V.L. Dawson*. "CHIP Regulates Leucine-Rich Repeat Kinase-2 (LRRK2) Ubiquitination, Degradation and Toxicity." Proc Natl Acad Sci U S A. 2009 Feb 5. [Epub ahead of print] 106: 2897-2902 (2009). PMID: 19196961

Tsang A.H., Y.I. Lee, H.S. Ko, J.M. Savitt, O. Pletnikova, J.C. Troncoso, V.L. Dawson, T.M. Dawson*, and K.K. Chung*. "S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease." [Epub 2009 Mar] Proc Natl Acad Sci U.S.A. 106(12):4900-5 (2009) PMID: 19273858 *Co-corresponding and senior authors.

Ng, C.-H., S.Z.S. Mok, C. Koh, Z. Quyang, M.I. Fivaz, E.-K. Tan, V.L. Dawson, T.M. Dawson, F. Yu and K.-L. Lim. "Parkin Protects Against LRRK2 Mutant-Induced Dopaminergic Neurodegeneration in Drosophila." J. Neuroscience, 29:11257-11262 (2009) PMID: 19741132.

Daher, J.P.L., M. Ying, R. Banerjee, R.S. McDonald, M.D. Hahn, L. Yang, M.F. Beal, B. Thomas, V.L. Dawson, T.M. Dawson, D.J. Moore. "Conditional Transgenic Mice Expressing C-terminally Truncated Human ?-Synuclein (?Syn119) Exhibit Reduced Striatal Dopamine without loss of Nigrostriatal Pathway Dopaminergic Neurons." Molecular Neurodegeneration, 4:34 (2009) PMID: 19630976.

Shin, J.-H., V.L. Dawson, T.M. Dawson, "SnapShot: Parkinson's Disease Pathogenesis." Cell, 139:440-440.e1 (2009) PMID: 19837042

Andres-Mateos, E., R. Mejias, M. Sasaki, X. Li, B.M. Lin, S. Biskup, L. Zhang, B. Thomas, L. Yang, G. Liu, M.F. Beal, D.L. Huso, T.M Dawson* and V.L. Dawson*. "Unexpected Lack of Hypersensitivity in. LRRK2 Knock-out Mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)" J. Neuroscience, 29:15846-15850 (2009) PMID: 20016100 *Co-corresponding and senior authors.

Xiong, Y., C.E. Coombes, A. Kilaru, A.D. Gitler, W.J. Bowers, V.L. Dawson, T.M. Dawson* and D.J. Moore* "GTPase Activity Plays a Key Role in the Pathobiology of LRRK2" PLoS Genetics, 2010 Apr 8;6(4):e1000902.PMID: 20386743 *Co-corresponding and senior authors.

Vives-Bauza, C., C. Zhou, Y. Huang, M. Cui, R.L.A. de Vries, J. Kim, J. May, M.A. Tocilescu, W. Liu, H.S. Ko, J. Magrane, D.J. Moore, V.L.Dawson, R. Grailhe, T.M. Dawson, C. Li, K. Tieu, S. Przedborski "PINK1-depedendent Recruitment of Parkin to mitochondria in mitophagy." Proc Natl Acad Sci U S A., 107:379-83 (2010). PMID: 19966284

Dawson, T.M., H.S. Ko, V.L. Dawson, "Genetic Animal Models of Parkinson's Disease." Neuron, 66:646-61 (2010). PMID: 20547124

Li, X., D.J. Moore, T.M. Dawson and V.L. Dawson "Reevaluation of Phosporylation Sites in the Parkinson's Disease Associated Leucine Rich Repeat Kinase-2." Journal of Biological Chemistry, J Biol Chem. 2010 Jul 1. [Epub ahead of print] PMID: 20595391

Lee, B.D., J.H. Shin, J. VanKampen, L. Petrucelli, A. B. West, H.S. Ko, Y.L. Lee, K.A. Maguire-Zeiss, W.J. Bowers, H. Federoff, V.L. Dawson and T.M. Dawson. "Inhibitors of Leucine Rich Repeat Kinase Protect Against Models of Parkinson's Disease." Nature Medicine, 16:998-1000 (2010) Aug 22. [Epub ahead of print] PMID: 20729864

Ko, H.S., Y. Lee, J.-H. Shin, S.S. Karuppagounder, B.S. Gadad, A.J. Koleske, O. Pletnikova, J.C. Troncoso, V.L. Dawson, T.M. Dawson. Phosphorylation by the c-Abl Protein Tyrosine Kinase Inhibits Parkin's Ubiquitination and Protective Function." Proc. Natl. Acad. Sci. U.S.A., published ahead of print September 7, 2010, doi:10.1073/pnas.1006083107; 107:16691-16696 (2010) PMID: 20823226.

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 regional Parkinson's disease community including Maryland, Washington DC, Virginia, West Virginia, Delaware, and South Central Pennsylvania. Consequently, 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 Capitol Area, the Delmarva Parkinson's Alliance, the Lancaster County Parkinson's Support Group, and the Baltimore Health Disparities Coalition. 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. 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. As an example, our annual symposium will be held in Lewes Delaware in conjunction with the newly formed Delmarva Parkinson's Alliance, a small coalition of eight groups on the Delmarva Peninsula. We anticipate 150 to 250 individuals in attendance. The majority of those attending have never had the opportunity to attend such a program. The local symposium attendance has grown to 450 annually as a result of collaboration, which allows us to leverage professional and financial resources. Educational initiatives which focus on professional education include the Edmund Safra Foundation Nurse Faculty Training in Parkinson's Disease, a December 2010 Delaware Nurse Conference, outreach to Area Health Education Centers, the provision of multiple training programs to local nursing homes, and the mentoring of 8-10 students from area universities including local institutions serving a largely minority population. Our center's outreach and education mission is committed to serving the broad and diverse regional Parkinson's community, which includes those living with the disease and their families. Caregiver training is offered annually, with the goal of eventually growing that program. All efforts 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.