The overall goals of this proposal are to understand the role of a-synuclein, parkin, LRRK2 and the relationship with oxidative stress in the pathogenesis and pathology of Parkinson's disease (PD) and to define the molecular mechanisms of neuronal injury in animal models of PD. The program represents a multi-disciplinary, mechanistic approach involving interactive, productive investigators with complementary areas of expertise who have long been committed to the studies of neurodegenerative diseases.
Our aim will be to integrate the activities of various disciplines such that the interrelationships will result in greater scientific contributions and achievements if each project were pursued individually. The program has one major theme: To understand the role of familial associated genes a-synuclein, parkin and LRRK2 in the pathogenesis of Parkinson's disease and related disorders. The role of a-synuclein, parkin, LRRK2 and oxidative stress 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. We believe that our multi-disciplinary approach has the capacity to produce unique information concerning the mechanisms of neurodegeneration in genetic animal models of Parkinson's disease and the related synucleinopathies and lead to better understanding of the function and the role of a-synuclein, parkin and LRRK2 in normal and pathophysiologic processes related to PD. The program consists of three projects: 1) Biology of Parkin and its Role in Parkinson's Disease;2) Mechanisms of Neurodegeneration in Human alpha-Synuclein Transgenic Mice;3) LRRK2 Biology in Parkinson's disease and four cores A) Administration and training, B) Bioenergetics, C) Transgenic and Neurobehavior and D) Clinical.

Public Health Relevance

Parkinson's Disease (PD) is a common progressive neurodegenerative disorder with no neuroprotective or neurorestorative therapy. Understanding the molecular mechanisms by which a-synuclein, parkin, LRRK2 and oxidative stress contribute to the degeneration of neurons in PD could lead to innovative therapies 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 #
3P50NS038377-14S1
Application #
8540518
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Sieber, Beth-Anne
Project Start
1998-09-30
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
14
Fiscal Year
2012
Total Cost
$121,500
Indirect Cost
$46,500
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Hinkle, Jared T; Perepezko, Kate; Rosenthal, Liana S et al. (2017) Markers of impaired motor and cognitive volition in Parkinson's disease: Correlates of dopamine dysregulation syndrome, impulse control disorder, and dyskinesias. Parkinsonism Relat Disord :
Panicker, Nikhil; Dawson, Valina L; Dawson, Ted M (2017) Activation mechanisms of the E3 ubiquitin ligase parkin. Biochem J 474:3075-3086
Dawson, Ted M; Dawson, Valina L (2017) Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics. Annu Rev Pharmacol Toxicol 57:437-454
Yun, Seung Pil; Kim, Hyojung; Ham, Sangwoo et al. (2017) VPS35 regulates parkin substrate AIMP2 toxicity by facilitating lysosomal clearance of AIMP2. Cell Death Dis 8:e2741
Sulzer, David; Alcalay, Roy N; Garretti, Francesca et al. (2017) T cells from patients with Parkinson's disease recognize ?-synuclein peptides. Nature 546:656-661
Liddelow, Shane A; Guttenplan, Kevin A; Clarke, Laura E et al. (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481-487
Xiong, Yulan; Dawson, Ted M; Dawson, Valina L (2017) Models of LRRK2-Associated Parkinson's Disease. Adv Neurobiol 14:163-191
Gwinn, Katrina; David, Karen K; Swanson-Fischer, Christine et al. (2017) Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program. Biomark Med 11:451-473
Ando, Maya; Fiesel, Fabienne C; Hudec, Roman et al. (2017) The PINK1 p.I368N mutation affects protein stability and ubiquitin kinase activity. Mol Neurodegener 12:32
Lee, Yunjong; Stevens, Daniel A; Kang, Sung-Ung et al. (2017) PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival. Cell Rep 18:918-932

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