- 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.
(RELEVANCE) Genetic and biochemical abnormalities of ?-synuclein account for the pathogenesis of PD. Thus, understanding how ?-synuclein abnormalities cause neuronal death in brain will provide better understanding about PD and lead to identification of potential therapeutic targets to treat PD.
Blauwendraat, Cornelis; Pletnikova, Olga; Geiger, Joshua T et al. (2018) Genetic analysis of neurodegenerative diseases in a pathology cohort. Neurobiol Aging : |
Heo, Seok; Diering, Graham H; Na, Chan Hyun et al. (2018) Identification of long-lived synaptic proteins by proteomic analysis of synaptosome protein turnover. Proc Natl Acad Sci U S A 115:E3827-E3836 |
Dawson, Ted M; Golde, Todd E; Lagier-Tourenne, Clotilde (2018) Animal models of neurodegenerative diseases. Nat Neurosci 21:1370-1379 |
Lee, Saebom; Kim, Sangjune; Park, Yong Joo et al. (2018) The c-Abl inhibitor, Radotinib HCl, is neuroprotective in a preclinical Parkinson's disease mouse model. Hum Mol Genet 27:2344-2356 |
Xiong, Yulan; Neifert, Stewart; Karuppagounder, Senthilkumar S et al. (2018) Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice. Proc Natl Acad Sci U S A 115:1635-1640 |
Yun, Seung Pil; Kam, Tae-In; Panicker, Nikhil et al. (2018) Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. Nat Med 24:931-938 |
Hinkle, Jared Thomas; Perepezko, Kate; Bakker, Catherine C et al. (2018) Onset and Remission of Psychosis in Parkinson's Disease: Pharmacologic and Motoric Markers. Mov Disord Clin Pract 5:31-38 |
Kam, Tae-In; Mao, Xiaobo; Park, Hyejin et al. (2018) Poly(ADP-ribose) drives pathologic ?-synuclein neurodegeneration in Parkinson's disease. Science 362: |
Sathe, Gajanan; Na, Chan Hyun; Renuse, Santosh et al. (2018) Phosphotyrosine profiling of human cerebrospinal fluid. Clin Proteomics 15:29 |
Guerreiro, Rita; Ross, Owen A; Kun-Rodrigues, Celia et al. (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17:64-74 |
Showing the most recent 10 out of 250 publications