Udall Center - Johns Hopkins School of Medicine

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Director: Ted M. Dawson, M.D., Ph.D.

Title: Udall Center of Excellence for Parkinson's Disease Research

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


Central Theme

Mutations in the alpha-synuclein, parkin, and LRRK2 genes have been linked to familial Parkinson's Disease (PD).  The Johns Hopkins Udall Center seeks to elucidate an understanding of the pathogenic mechanisms underlying PD by identifying the molecular mechanisms through which associated gene mutations act, as well as their relationship to the common sporadic form of PD.
 

Center Structure 

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. 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), a-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. 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.

The Center is comprised of four Research Projects and four supportive Cores. Research Projects include: Project 1: Biology of parkin and its role in Parkinson’s disease (Ted M. Dawson); Project 2: Understanding mechanisms of α-synuclein pathology (Han Seok Ko); Project 3: Establishing clinical utility of CSF biomarkers for PD (Akhilesh Pandey); Project 4: LRRK2 Biology in Parkinson’s Disease (Valina L. Dawson). Cores include: Administrative (Ted M. Dawson); Clinical (Liana Rosenthal); Neuropathology (Juan C. Troncoso); and Proteomics (Akhilesh Pandey)
 

Recent Advances

  • Discovery of the mechanism of internalization of pathologic a-synuclein through lymphocyte activation gene 3
  • Generation of animal and cellular models of the genetic causes of PD, including. adult conditional knockouts of parkin neurodegeneration in PD that have deficits in mitochondrial biogenesis in dopamine neurons
  • Identification of novel targets to slow the progression of PD by targeting the molecular mechanisms by which genetic mutations cause PD
     

Public Health Statement

Tremendous advances in understanding th pathogenesis of a variety of neurodegenerative disorders have been made by the study of the 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. Most importantly for this proposal, mutations in alpha-synuclein, parkin and LRRK2 have been linked to familial Parkinson's Disease (PD). The Johns Hopkins 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.  
 

Budget End Date: 2019/07/31

NIH Grant Number: P50 NS038377