- PROJECT 2: UNDERSTANDING MECHANISMS OF ? -SYNUCLEIN PATHOLOGY Genetic and biochemical abnormalities of ?-synuclein are directly implicated in the pathogenesis of familial and sporadic forms of Parkinson's disease (PD). The underlying mechanisms of ?-synuclein-induced neurodegeneration are poorly understood. Familial mutations in ?-synuclein as well as oxidative and nitrosative stress contribute to ?-synuclein pathology, in part, via enhanced oligomerization, fibrillation and aggregation. During the last funding cycle, we showed in collaboration with Project 1 that activation of the non- receptor tyrosine kinase, c-Abl may contributes to the pathogenesis of PD. From these studies emerged the exciting preliminary findings that c-Abl phosphorylates ?-synuclein at tyrosine 39. However, the potential roles of tyrosine 39 ?-synuclein and c-Abl activation in pathogenesis of PD has not been explored. We will study the roles of phosphorylation of ?-synuclein at tyrosine 39 and c-Abl activation in the death of DA neurons due to ?- synuclein, as well as, their roles in aggregation of ?-synuclein in vitro and in vivo. With the Proteomics Core D, the Clinical Core B and the Neuropathology Core C, we will investigate whether the levels of phosphorylation of ?-synuclein at tyrosine 39 can serve as a progression and/or pathologic maker of ?-synuclein-induced neurodegeneration and of ?-synuclein pathology in human PD. For these studies, we will assess the levels of tyrosine 39 phosphorylation of ?-synuclein and the activation state of c-Abl in human A53T ?-synuclein transgenic model, the adeno-associated virus-WT or A53T ?-synuclein model with DA neuron loss, and human post-mortem tissues from PD patients via a phosphospecific tyrosine 39 ?-synuclein antibody and MRM (Multiple Reaction Monitoring) mass spectrometry. Cell-to-cell transmission of misfolded ?-synuclein may contribute to the degeneration of DA neurons in sporadic PD and the mechanisms accounting for the recruitment and the corruption of endogenous ?-synuclein into fibrils are not known. Since our preliminary data suggests that tyrosine 39 phosphorylation of ?-synuclein by c-Abl promotes the fibrillation of ?-synuclein, we will study the ability of WT versus phospho-deficient Y39F and phospho-mimetic ?-synuclein Y39E, as well as c-Abl deficiency in cell-to-cell transmission and degeneration of DA neurons in the ?-synuclein PFF model of sporadic PD. Finally, we will explore proteomic changes induced by ?-synuclein PFFs in degenerating DA neurons via advanced spike-in mass spectrometry approaches combined with SILAM (Stable Isotope Labeling in Mammals). These studies will provide new mechanistic insights into the pathogenesis of ?-synuclein induced neurodegeneration and may lead to the development of novel therapeutic targets and biomarkers for the treatment of PD.

Public Health Relevance

(RELEVANCE) Genetic and biochemical abnormalities of a-synuclein account for the pathogenesis of PD. Thus, understanding how a-synuclein abnormalities cause neuronal death in brain will provide better understanding about PD and lead to identification of potential therapeutic targets to treat PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
2P50NS038377-16
Application #
8882846
Study Section
Special Emphasis Panel (ZNS1-SRB-J (07))
Project Start
Project End
Budget Start
2014-09-30
Budget End
2015-07-31
Support Year
16
Fiscal Year
2014
Total Cost
$372,600
Indirect Cost
$142,600
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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