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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

The theme of the Udall Center at Johns Hopkins University School of Medicine is 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.

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 Project 2 focuses on in vitro and in vivo models, of alpha-synuclein biology and Project 3 focuses on in vitro and in vivo models LRRK2 biology.

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 Research 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 (Liana Rosenthal 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
  • Identification of LRRK2 Phosphosubstrates
  • Discovery of PARIS
  • Discovery that Parthanatos plays an important role in the degeneration of dopamine neurons in PD

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

To continue advancing the overall goals of this proposal, which are:

  1. To study and characterize parkin and the role of parkin substrates (AIMP2 and PARIS) in the pathogenesis of Parkinson’s disease (PD) using cellular models, transgenic mice, adult conditional parkin knockout mice and human postmortem material from PD patients, patients with parkinsonism and aged-matched controls.
  2. To explore the role of c-Abl activation in the pathogenesis of alpha-synuclein-induced degeneration in PD and related synucleinopathies by characterizing cellular and transgenic models of alpha-synuclein induced neurodegeneration and examining human postmortem material from PD patients, patients with parkinsonism and aged-matched controls.
  3. To study and characterize LRRK2, identify LRRK2 interacting proteins and substrates and determine their role in the pathogenesis of Parkinson’s disease (PD) using cellular models, transgenic mice, adult conditional parkin knockout mice and human postmortem material from PD patients, patients with parkinsonism and aged-matched controls. 

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 and movement disorder 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 National Parkinson Foundation, National Ataxia Foundation, Parkinson Foundation of the National Capital Area (PFNCA), Cure PSP, the Delmarva Parkinson’s Alliance, the Lancaster County Parkinson’s Support Group, the Baltimore Health Disparities Coalition, and the newly formed Maryland Association for Parkinson’s Support. Our Center has become the regional resource for lay individuals wanting to establish a support group. In this role we typically provide consultation to four to six leaders per year. The guidance that we provide has led to a robust regional network of support. 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 500 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.

Johns Hopkins University telemedicine efforts have provided telemedicine to individuals directly in their communities and even their homes throughout the Unites States and internationally. The viability of telemedicine to serve a greater population of individuals throughout the world will be studied as a result of a recent grant from the Patient Centered Outcomes Research Institute awarded to the National Parkinson Foundation. The relationships that our Udall Center has established with the regional network of those underserved populations provided the pilot populations for regional telemedicine initiatives. Community outreach relationships have been built since the inception of the Udall Center here at the Johns Hopkins University. Our Center will continue to participate in this research with the National Parkinson Foundation and consequently provide improved services to those underserved in this region. By improving access to specialty neurologists and the allied team, we hope to improve the quality of care available to all patients living with PD.

Faculty and staff provide about 150 speaking engagements each year to support groups and professional groups.  These speaking engagements provide the opportunity to forge relationships and share knowledge with new providers as well as recruit for ongoing research initiatives. Some of the new and significant contacts made within the past year include: pharmacists; Maryland state nursing home ombudsmen; nursing faculty; graduate and undergraduate nursing students; and primary care physicians. Nurse Practitioners attending the Johns Hopkins School of Nursing receive a yearly lecture on Parkinson’s and Movement Disorders presented by our Center nurses. Our nursing professionals are serving as a resource and experts for a new class for undergraduate nursing students on Parkinson’s disease being offered at Towson University. Center Faculty routinely lecture to regional and international providers.

Lay community outreach has focused on bringing the Parkinson’s Disease 101 educational program and our symposium to rural areas. We are the leading institution coordinating a fall 2013 symposium in Lancaster Pennsylvania in collaboration with the University of Pennsylvania, Hershey Medical Center, and the Lancaster County Support group. The support group leadership has been requesting such a program for their community for the past four years. All Center faculty and staff will participate. The Parkinson’s Disease 101 programs were offered at three rural locations were attended by 170 individuals. The Center print newsletter is distributed to well over 2000 and the electronic newsletter to a growing population of close to 400. Our charity team, Pacing for Parkinson’s, within the Baltimore Running Festival has close to 200 participants this year. This significant awareness event contributes to enhanced knowledge of resource availability and research opportunities for the lay public. We will participate in the Senior Exposition this fall which reaches 4-6,000 seniors, again creating awareness.

Select Recent Publications

Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss.
Lee Y, Karuppagounder SS, Shin JH, Lee YI, Ko HS, Swing D, Jiang H, Kang SU, Lee BD, Kang HC, Kim D, Tessarollo L, Dawson VL, Dawson TM. Nat Neurosci. 2013 Oct;16(10):1392-400. PMID: 23974709

New synaptic and molecular targets for neuroprotection in Parkinson's disease.
Calabresi P, Di Filippo M, Gallina A, Wang Y, Stankowski JN, Picconi B, Dawson VL, Dawson TM.
Mov Disord. 2013 Jan;28(1):51-60. PMID: 22927178

Sulfhydration mediates neuroprotective actions of parkin.
Vandiver MS, Paul BD, Xu R, Karuppagounder S, Rao F, Snowman AM, Ko HS, Lee YI, Dawson VL, Dawson TM, Sen N, Snyder SH. Nat Commun. 2013;4:1626. PMID: 23535647 Free PMC Article

Last updated October 31, 2013