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Project 2: Understanding Mechanisms of Alpha-synuclein Pathology

Genetic and biochemical abnormalities of α-synuclein are directly implicated in the pathogenesis of familial and sporadic forms of Parkinson’s disease (PD). The underlying mechanisms of α-synuclein-induced neurodegeneration are poorly understood. Familial mutations in α-synuclein as well as oxidative and nitrosative stress contribute to α-synuclein pathology, in part, via enhanced oligomerization, fibrillation and aggregation. Previously, they showed in collaboration with Project 1 that activation of the nonreceptor tyrosine kinase, c-Abl may contributes to the pathogenesis of PD. From these studies emerged the exciting preliminary findings that c-Abl phosphorylates α-synuclein at tyrosine 39. However, the potential roles of tyrosine 39 α-synuclein and c-Abl activation in pathogenesis of PD has not been explored. 
 
Project 2 proposes to study the roles of phosphorylation of α-synuclein at tyrosine 39 and c-Abl activation in the death of DA neurons due to α-synuclein, as well as, their roles in aggregation of α-synuclein in vitro and in vivo. In collaboration with the Proteomics Core D, the Clinical Core B and the Neuropathology Core C, they will investigate whether the levels of phosphorylation of α-synuclein at tyrosine 39 can serve as a progression and/or pathologic maker of α-synuclein-induced neurodegeneration and of α-synuclein pathology in human PD.
 
For these studies, they will assess the levels of tyrosine 39 phosphorylation of α-synuclein and the activation state of c-Abl in transgenic models and human post-mortem tissues from PD patients via a phosphospecific tyrosine 39 α-synuclein antibody and MRM (Multiple Reaction Monitoring) mass spectrometry. 

They will also investigate the cell-to-cell transmission of misfolded α-synuclein as this may be a cause of degeneration of DA neurons in the α-synuclein PFF model of sporadic PD for which the mechanism is currently unknown. Finally, they will explore proteomic changes induced by α-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 α-synuclein induced neurodegeneration and may lead to the development of novel therapeutic targets and biomarkers for the treatment of PD.

Team Members

Han Seok Ko, PhD (Principal Investigator)
Saurav Brahmachari, PhD (Research Staff)
Seung Pil Yun (Research Staff)

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