|Department Affiliations||Neurology, Neuroscience, Physiology, Institute for Cell Engineering|
|SOM Address||Suite 719 Miller Research Building|
My laboratory is actively engaged in discovering and defining cell signaling pathways that lead to either neuronal survival or neuronal death. We have characterized neuronal injury and survival pathways in cell, fly and mouse models of Parkinson’s disease and stroke. We have explored the role of the monogenic forms of Parkinson’s disease with a focus on parkin, DJ-1 and LRRK2 in order to begin to define the biochemical signaling important to Parkinson’s disease. We have developed yeast, cellular, fly and mouse models to explore the LRRK2 disease causing mutations. We have extended our investigations into human postmortem tissue and recently we have incorporated new technologies in stem cell biology to generate human neuronal cultures derived from reprogrammed patient fibroblasts and human embryonic stem cells to explore survival and disease signaling events relevant to Parkinson’s disease and stroke as well as to define neuron survival networks.
My laboratory has defined the excitotoxic signaling pathway mediated by nitric oxide, poly(ADP-Ribose) polymerase and apoptosis inducing factor and named it Parthanatos, to distinguish it from other distinct forms of cell death including apoptosis, autophagy and necrosis. We identified and characterized new survival molecules which include transcription factor NFIA, a novel E3 ligase Iduna, a novel Notch regulatory protein Botch and a novel AAA+ ATPase Thorase that acts to disassemble the GRIP1/GluR2 complex, thus regulating excitability, plasticity and behavior, as well as a microRNA, mIR-223 that regulates neuronal survival in part through regulation of glutamate receptor expression. Recently we have found overlap between our investigations in Parthanatos and Parkinson’s disease in that age dependent loss of dopamine neurons due to expression of the parkin substrate AIMP2 is dependent on Parthanatos. We are currently exploring if Parthanatos generally contributes to DA neurodegeneration and PD and have exciting new preliminary data that Parthantos is a common feature in many PD models as well as in human PD postmortem tissue.
To explore these questions we employ advanced technologies in high throughput screening, next generation sequencing including RNA Seq and ChIP Seq, ribosomal foot printing, and high throughput proteomic analysis coupled with advanced computational biology to investigate signaling networks in nitric oxide and PAR signaling and in models of PD. The overarching goal of the research in my laboratory is to understand death and survival signaling in order to identify new targets for therapeutic development.
- Chi, Z., S.T. Byrne, A. Dolinko, M.M. Harraz, M-S Kim, G. Umanah, J. Zhong, R. Chen, J. Zhang, J. Xu, L. Chen, A. Pandey, T.M. Dawson and V.L. Dawson. “Botch is a -glutamyl Cyclotransferase that Deglycinates and Antagonizes Notch” PMID: 24767995, Cell Reports, 7:681-688 (2014).
- Martin, I, J.W. Kim, B.D. Lee, H. Kang, J-C Xu, H. Jia, J. Stankowski, M- Kim, J. Zhong, M. Kumar, S. Andrabi, D.W. Dickson, Z.K. Wszolek, A. Pandey, T.M. Dawson, and V.L. Dawson. “Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson’s disease.” PMID: 24725412 Cell, 157(2):472-85 (2014).
- Lee, Y-I , D. Giovinazzo, H.C. Kang, Y. Lee, J.S. Jeong, P-T Doulias, Z. Xie, J. Hu, M. Ghasemi, H. Ischiropoulos, J. Qian, H. Zhu, S. Blackshaw, V.L. Dawson, T.M. Dawson. “Protein Microarray Characterization of the S-Nitrosoproteome.” PMID: 24105792 (EPub Oct 2013) Mol. Cell. Proteomics 13(1):63-72 (2014).
- Lee, Y., S.S. Karuppagounder, J.-H. Shin, Y.-I. Lee. H.S. Ko, D. Swing, B.D. Lee. H.C. Kang, L. Tessarollo, V.L. Dawson and T.M. Dawson, “Parthanatos Mediates AIMP2 Activated Age Dependent Dopaminergic Neuronal Loss.” PMID: 23974709 (Epub Aug 2013) Nature Neurosci., 16:1392-1400 (2013).