Parkinson's disease (PD) is relentlessly progressive and despite effective symptomatic therapy in the early stages of the illness most patients have substantial morbidity and disability. 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. Our hypothesis is that a-synuclein, parkin and LRRK2 contribute to a complex signaling network that results in the pathogenesis of Parkinson's Disease and related disorders. The center will approach this hypothesis in a multidisciplinary manner. The center 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. Our center will integrate diverse advanced technologies within the center to accelerate discovery. It will work collaboratively within the Udall Center Network to accelerate discovery of disease, new therapies and disease and progression biomarkers. Through the integration of the activities of the various disciplines, the interrelationships will result in a greater scientific contribution than could be achieved if each project or center investigation were pursued individually. The Johns Hopkins Udall Center will serve as a local and national resource for PD research including broad sharing of data and clinical and biospecimen resources and fostering community outreach activities. We will provide and coordinate training of young investigators in the pathogenesis and study of Parkinson's disease and Parkinson's syndromes. The Johns Hopkins Udall Center is focused on understanding the interrelationship between parkin (Project 1), the most common cause of autosomal recessive PD, ?-synuclein (Project 2), which is causal in sporadic PD and LRRK2 (Project 4), the most common cause of autosomal dominant PD 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 ?-synuclein, parkin, and LRRK2 in normal and pathophysiologic processes related to PD.

Public Health Relevance

Due to the significant impact on the quality of patients' lives and their families as well as 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. Deploying a multi-disciplinary approach the Center will investigate the role of ?-synuclein; parkin and LRRK2 in the pathogenesis of Parkinson's Disease and related disorders while providing training of young investigators and serving as a local and national resource. The goals of the Center are to discover disease and progression biomarkers that can be used clinically and to identify key events in the neurodegenerative network that could be therapeutically targeted to slow or halt the progression of PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
2P50NS038377-16
Application #
8882840
Study Section
Special Emphasis Panel (ZNS1-SRB-J (07))
Program Officer
Sieber, Beth-Anne
Project Start
1998-09-30
Project End
2019-07-31
Budget Start
2014-09-30
Budget End
2015-07-31
Support Year
16
Fiscal Year
2014
Total Cost
$2,430,000
Indirect Cost
$930,000
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Mills, Kelly A; Mari, Zoltan; Bakker, Catherine et al. (2016) Gait function and locus coeruleus Lewy body pathology in 51 Parkinson's disease patients. Parkinsonism Relat Disord 33:102-106
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Karuppagounder, Senthilkumar S; Xiong, Yulan; Lee, Yunjong et al. (2016) LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity. J Chem Neuroanat 76:90-97
Davis, Marie Y; Johnson, Catherine O; Leverenz, James B et al. (2016) Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. JAMA Neurol 73:1217-1224
Nucifora Jr, Frederick C; Nucifora, Leslie G; Ng, Chee-Hoe et al. (2016) Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1. Nat Commun 7:11792
Mills, Kelly A; Mari, Zoltan; Pontone, Gregory M et al. (2016) Cognitive impairment in Parkinson's disease: Association between patient-reported and clinically measured outcomes. Parkinsonism Relat Disord 33:107-114

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