Assistant Professor of Neurobiology and Anatomy
Neurobiology of Disease
Signal transduction mechanism in the nervous system focusing on the role of GPI-anchored proteins and their regulatory enzymes on neuron-glia communication
Cell to cell communication and signal transduction are crucial for many of biological processes of unicellular and multicellular organisms and largely mediated by proteins decorating the cell surface. About 10-20% of surface protein is attached to the plasma membrane by glycosylphosphatidylinositol (GPI) anchor. GPI anchor is a glycolipid structure containing phosphoethanolamine, a glycan core and a phosphatidylinositol tail. GPI-anchored proteins play roles in numerous signaling pathways including Notch, shh, BMP, FGF, Wnt, GDNF and JAK-STAT, which are critical during development and adulthood. Despite the conservation, abundance and importance of GPI anchorage, the mechanisms regulating GPI-anchored proteins and their downstream signaling are largely unknown. Currently, a family of recently identified glycerophosphodiester phosphodiesterase (GDE) enzymes is the only known regulator of surface GPI-anchored proteins in vertebrates. Phenotypic analyses of GDE null animals have begun to reveal critical roles of GPI-anchored proteins in multiple processes including neurogenesis, gliogenesis, synapse maturation and neurodegeneration.
The overall goals of my lab are to:
- Characterize the enzymatic properties of a family of GDE enzymes that shed GPI anchors from the plasma membrane.
- Study the role of GPI-anchored proteins in the nervous system focusing on neuron-glial interactions.
- Develop novel biochemical tools to identify substrate GPI-anchored proteins using a bacterial toxin which strongly binds GPI structures.
- Identify pharmacological modulators of GDE enzymes using high-throughput drug screens.
To achieve these goals, we use multidisciplinary approaches including biochemical fractionation and affinity purification of enzymes and substrates, bacterial expression systems, in vitro heterologous cell culture, primary neuron/astrocyte/oligodendrocyte culture, in ovo electroporation, in vivo genetic approaches and high throughput screens. We expect the studies in our lab will reveal previously unappreciated functions of GPI anchorage and its regulation by GDEs in various signaling pathways of normal and disease conditions.
Choi, J., Park, S., and Sockanathan, S. (2014) Activated retinoid receptors are required for the migration and fate maintenance of subsets of cortical neurons. Development, 141:1151-1160.
Park, S.*, Lee, C.*, Sabharwal, P., Zhang, M., Meyers, C.L., and Sockanathan, S. (2013b) GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK. Science, 339:324-328.
Park, J.M., Hu, J.H., Milshteyn, A., Zhang, P.W., Moore, C.G., Park, S., Datko, M.C., Domingo, R.D., Reyes, C.M., Wang, X.J., et al. (2013a) A prolyl-isomerase mediates dopamine-dependent plasticity and cocaine motor sensitization. Cell, 154:637-650.
Rodriguez, M., Choi, J., Park, S., and Sockanathan, S. (2012) Gde2 regulates cortical neuronal identity by controlling the timing of cortical progenitor differentiation. Development, 139:3870-3879.
Sabharwal, P., Lee, C., Park, S., Rao, M., and Sockanathan, S. (2011) GDE2 regulates subtype-specific motor neuron generation through inhibition of Notch signaling. Neuron, 71:1058-1070.
Hu, J.H.*, Park, J.M.*, Park, S.*, Xiao, B., Dehoff, M.H., Kim, S., Hayashi, T., Schwarz, M.K., Huganir, R.L., Seeburg, P.H., et al. (2010) Homeostatic scaling requires group I mGluR activation mediated by Homer1a. Neuron, 68:1128-1142.
Park, S.*, Park, J.M.*, Kim, S., Kim, J.A., Shepherd, J.D., Smith-Hicks, C.L., Chowdhury, S., Kaufmann, W., Kuhl, D., Ryazanov, A.G., et al. (2008) Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron, 59:70-83.
*: equal contribution