Alican Gümürdü, MSc Student
Ramazan Yıldız, MSc Student
|Ramazan, Deniz, Alican, Yongsoo. Feb. 2016||Erdem, Yongsoo, Ramazan, Alican. Dec. 2016|
Vesicles that contain neurotransmitters in neurons are nanomachines (synaptic vesicles, 45 nm in diameter) to deliver neurotransmitters into the extracellular target by a membrane fusion process. How these vesicles fuse with the membrane has been controversial and the molecular mechanism of vesicle fusion remains not fully understood. In addition, psychiatric disorders result from the high level of neurotransmitters and the hyperactivity of vesicle fusion. However, it has been impossible to find therapeutics to regulate vesicle fusion in a neuronal disease condition.
My overall goals are to translate basic research into diagnosis and therapeutics for psychiatric disorders by controlling neurotransmitter release using synthetic biology. Synthetic biology is an emerging scientific method to understand how life works. Bottom-up synthetic biology is an in vitro-based approach that uses minimal machinery to reconstitute cellular processes. This approach reconstitutes minimal systems to understand how they work. Bottom-up synthetic biology (also called reductionism) can explain the molecular mechanisms and reveal how biomolecules work.
Synthetic neurotransmission and the interdisciplinary techniques are the basis for my confidence that I will make significant progress in tackling unsolved problems in diagnosis and therapeutics for psychiatric disorders.
To this end, I have established the synthetic neurotransmission to reconstitute and reconstruct the vesicle fusion process with native vesicles, i.e. synaptic vesicles and large dense-core vesicles. My research interests are to develop novel therapeutics that control neurotransmitter release for psychiatric disorders. Botulinum neurotoxin inhibiting vesicle fusion by cleaving SNARE proteins has been used in clinics and cosmetic market, but the side effect is the complete inhibition of vesicle fusion without specificity. We will develop chemical Botox or peptide Botox which selectively inhibits DCV fusion in psychiatric disorder condition because psychiatric disorders result from the hyperactivity of neurotransmitter stored in DCVs, i.e. adrenaline, dopamine, and serotonin (not stored in synaptic vesicle).
1) I have established the bottom-up synthetic neurotransmission and showed the complete reconstitution of vesicle fusion using purified native vesicles. We first reported that ATP is required for Ca2+-dependent fusion by preventing back-binding of synaptotagmin-1 to vesicle membrane (Park et al., Nature Struct Mol Biol, 2012).
2) What makes differences between in-vitro and in vivo? I found that the protein-membrane interaction in reconstitution system can vary depending on a buffer and lipid composition. Very surprisingly, we observed that low ionic strength environment causes artifact in proteins-proteins and proteins-membrane electrostatic interaction and showed the molecular mechanisms how vesicle fusion occurs (Park et al., Nature Struct Mol Biol, 2015).
|AWARDS AND RECOGNITION
• Co-Funded Brain Circulation Scheme Fellowship, (TUBITAK, Ankara, Turkey) and EU 7th Frame Work Marie Curie Actions (Brussels, Belgium) (2016)
• EMBO Installation Grant (2016)
• Research fellowship for post-doctoral researcher, Alexander von Humboldt Foundation (2010 – 2012)
• Scholarship from KOSEF, KOREA SCIENCE AND ENGINEERING FOUNDATION (2008)
• The 8th Scholarship for natural sciences and engineering Ph.D. students from KBS (Korean Broadcasting System, South Korea) (2008)
Full list and citations: Google Scholar: Yongsoo Park
• Gümürdü A., Yildiz R., Eren E., Karakülah G., Ünver T., Genç Ş. & Park Y. MicroRNA exocytosis by large dense-core vesicle fusion. Scientific Reports. 2017 Mar 30; 7:45661. doi:10.1038/srep45661.
• Park Y, Seo JB, Fraind A, Pérez-Lara A, Yavuz H, Han K, Jung SR, Kattan I, Walla PJ, Choi MY, Cafiso DS, Koh DS, Jahn R. Synaptotagmin-1 binds to PIP2-containing membrane but not to SNAREs at physiological ionic strength. Nature Struct Mol Biol. 2015 in press.
• Ryu JK, Min D, Rah SH, Kim SJ, Park Y, Kim H, Hyeon C, Kim HM, Jahn R, Yoon TY. Spring-loaded unraveling of a single SNARE complex by NSF in one round of ATP turnover. Science. 2015 Mar 27;347(6229):1485-1489.
• Park Y, Vennekate W, Yavuz H, Preobraschenski J, Hernandez JM, Riedel D, Walla PJ, Jahn R. α-SNAP interferes with the zippering of the SNARE membrane fusion machinery. J Biol Chem. 2014 Jun 6;289(23):16326-16335.
• Park Y, Hernandez J. M, van den Bogaart G, Ahmed S, Holt M, Riedel D, and Jahn R. Controlling synaptotagmin activity by electrostatic screening. Nature Struct Mol Biol. 2012 Oct;19(10):991-7.
• Park Y and Kim KT. Dominant role of lipid rafts L-type calcium channel in activity-dependent potentiation of large dense-core vesicle exocytosis. J Neurochem. 2009 Jul;110(2):520-9.
• Park Y and Kim KT. Short-term plasticity of small synaptic vesicle (SSV) and large dense-core vesicle (LDCV) exocytosis. Cell Signal (Review article). 2009 Oct;21(10):1465-70.
• Park YS, Choi YH, Park CH, Kim KT. Non-genomic glucocorticoid effects on activity-dependent potentiation of catecholamine release in chromaffin cells. Endocrinology. 2008 Oct;149(10):4921-7.
• Park YS, Hur EM, Choi BH, Kwak E, Jun DJ, Park SJ, Kim KT. Involvement of protein kinase C-epsilon in activity-dependent potentiation of large dense-core vesicle exocytosis in chromaffin cells. J Neurosci. 2006 Aug 30;26(35): 8999-9005.
• (Cover article) Park YS, Jun DJ, Hur EM, Lee SK, Suh BS, Kim KT. Activity-dependent potentiation of large dense-core vesicle release modulated by mitogen-activated protein kinase(MAPK)/ERK signaling. Endocrinology. 2006 Mar;147(3):1349-56.
• Hur EM, Park YS, Huh YH, Yoo SH, Woo KC, Choi BH, Kim KT. Junctional membrane inositol 1,4,5-trisphosphate receptor complex coordinates sensitization of the silent EGF-induced Ca2+ signaling. J Cell Biol. 2005 May 23;169(4):657-67.