Udall Center - Johns Hopkins School of Medicine

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Director: Ted M. Dawson, MD, PhD

Title: The Morris K Udall Parkinson’s Disease Research Center of Excellence

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

Budget End Date: 7/31/2019

Central Theme

A major goal of the Johns Hopkins Udall Center is to understand the interrelationship between three genes associated with risk for Parkinson’s Disease (PD), and to use related discoveries to develop disease and progression biomarkers and, ultimately, new therapies.  The three genes being characterized include: a-synuclein, which is causal in sporadic PD; parkin, the most common cause of autosomal recessive PD; and LRRK2, the most common cause of autosomal dominant PD. 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 PD genes, as well as the opportunity to elucidate potential common pathways that may provide the best opportunities for identification of comprehensive new biomarkers and therapies. This 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 investigators with complementary areas of expertise and longstanding commitment 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 and four integral Cores:

Project 1: The biology of parkin and its role in Parkinson’s Disease (Ted M. Dawson, MD, PhD) proposes to investigate whether parkin inactivation in sporadic PD by nitrosative/oxidative stress, and c-Abl activation leads to parkin phosphorylation and inactivation causing the accumulation of parkin substrates, loss of mitochondrial quality control and toxicity in parallel with alpha-synuclein aggregation which leads to mitochondria dysfunction and subsequent toxicity.

Project 2: Understanding mechanisms of α-synuclein pathology (Han Seok Ko, PhD) proposes to study the roles of phosphorylation of α-synuclein at tyrosine 39 and c-Abl activation in the death of DA neurons due to α-synuclein, as well as their roles in aggregation of α-synuclein in vitro and in vivo.

Project 3: Establishing clinical utility of cerebrospinal (CSF) biomarkers for PD (Akhilesh Pandey, MD, PhD) proposes that dysregulation of c-Abl signaling cascade is intrinsically linked to PD pathogenesis and that the relative phosphorylation state of downstream c-Abl substrates, α-synuclein and parkin, should provide a sensitive read-out for the presence and/or the severity of PD.

Project 4: LRRK2 biology in Parkinson’s Disease (Valina L. Dawson, PhD). will address mechanisms of how aberrant kinase activity leads to disease, specifically, to determine if disease causing LRRK2 mutation G2019S elicits translational deregulation through pathogenic phosphorylation of s15, leading to altered protein expression and neuronal dysfunction and death.

Four Cores provide support for Center activities, including Administrative (Dr. TM Dawson); Clinical (Liana Rosenthal, MD); Neuropathology (Juan Troncoso, MD) and Proteomics (Dr. Pandey).

Research at the Johns Hopkins Udall Center addresses numerous research priorities from NINDS PD2014, including but not limited to:

  • Basic Research Recommendation 2, Elucidate the normal and abnormal function of ɑ-synuclein and its relationship to other PD genes
  • 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.
  •  Clinical Research Recommendation 4, Develop biomarkers of target engagement …for use in early-stage clinical trials.

Publications from the Johns Hopkins Udall Center

Resources Available

  • Animal Models
    • Parkin Knockouts (Germline and Conditional)
    • DJ-1 Knockouts
    • Alpha-Synuclein Transgenics
    • LRRK2 Knockouts
    • LRRK2 Transgenics
    • AIMP2 Transgenics
    • Lag 3 Knockouts
  • Human postmortem brain tissue (PD and related disorders)
  • Stable Cell Culture Models
  • Expression constructs for most PD related genes
  • Antibody production
  • Viral Expression Systems
  • iPSC models of PD
  • a-synuclein Pre-formed Fibrils (PFF)

Public Health Statement

It is estimated that Parkinson’s Disease (PD) affects more than 500,000 individuals in the United States; in 2010, the total annual costs 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 develop substantial disability. Due to the significant impact on the patients’ lives and those of 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, and ultimately preventive, therapies can be developed.

Tremendous advances in understanding a variety of neurodegenerative disorders have been made by the study of genes implicated in familial degenerative disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease.  Most importantly for this research effort, mutations in ɑ-synuclein, parkin and LRRK2 have been directly linked to familial PD.  The JHMI Udall Center has chosen to focus on the most common autosomal recessive (parkin) and autosomal dominant PD (LRRK2) linked genes plus ɑ-synuclein due to its potential role in both familial and sporadic (without prior family history) disease. Understanding the molecular mechanisms by which mutations in these three genes and their relationship to the more common sporadic form of PD has significant potential to enhance our understanding of the causes, progression and improved treatments for PD.

For further information: hopkinspdmd@jhmi.edu