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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.
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