Project 1: Biology of Parkin and Its Role in Parkinson's Disease Mutations in the parkin gene play a prominent role in Parkinson's disease (PD) as mutations in parkin are the main genetic cause of autosomal recessive PD and mutations in parkin also appear to play a role in familial PD. Parkin plays a pivotal role in the ubiquitin proteasomal pathway (UPP) by functioning as an ubiquitin E3 ligase. Most disease causing mutations of parkin are thought to be loss of function mutations that ultimately lead to the absence of ubiquitination and the subsequent failure of UPP-mediated degradation of parkin substrates. Thus, the abnormal accumulation of parkin substrates could play a role in the demise of substantia nigra dopaminergic neurons in patients with parkin mutations. Moreover, inactivation of parkin through dopaminergic and oxidative and nitrosative stress may play a role in sporadic PD. The stress activated non-receptor tyrosine kinase c-Abl phosphorylates and inactivates parkin and may play a critical role in sporadic PD by inactivating parkin. We propose to characterize the role of c-Abl mediated inactivation of parkin and its relationship to oxidative and nitrosative stress in sporadic PD as well as the role of parkin substrates in the pathogenesis of PD. Understanding the function and role of c-Abl and oxidative/nitrosative stress mediated inactivation of parkin may provide novel therapeutics targets to prevent the toxic effects of parkin deficiency in the degenerative process of PD.

Public Health Relevance

Parkinson Disease (PD) is common neurodegenerative disease with no proven neuroprotective or neurorestorative therapy. Understanding the molecular mechanisms by which parkin inactivation leads to PD may provide novel therapeutic opportunities to maintain parkin in a catalytically active neuroprotective state.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
3P50NS038377-14S1
Application #
8540519
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
2012-08-01
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
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Panicker, Nikhil; Dawson, Valina L; Dawson, Ted M (2017) Activation mechanisms of the E3 ubiquitin ligase parkin. Biochem J 474:3075-3086
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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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