Our research interests have focused on the molecular mechanism of the regulated secretory process and the pathogenesis of Parkinson’s disease (PD). Our laboratory has been using chromaffin cells and PC12 cells as model systems to study the molecular machinery of Ca2+-dependent exocytosis for many years. The accumulated information and experience in the study of these catecholaminergic cells have prompted our study moving from the mechanistic study in model systems to the understanding of the dopamine system in brain under physiological and pathological conditions, mainly PD in which the degeneration of dopaminergic neurons is the primary cause. Our research focuses on the role of α-synuclein in the pathogenesis of PD. The specific projects currently working in the laboratory are:
1. Role of a-synuclein in regulated secretion - We have performed a detailed characterization of the role of Rab3A and its relationship with Munc13 and Munc18 during vesicle priming before the occurrence of exocytosis based on the total internal reflection fluorescence microscope images obtained. a-Synuclein is a protein that present in Lewy body and Lewy neurites. Evidence supports that a-synuclein is involved in neurotransmitter release by regulated secretion. The goal is to clearly define how a-synuclein interacts with the individual molecules and where a-synuclein acts in the various steps occurred during exocytosis.
2. Association between the physiological function of a-synuclein and the degeneration of DA neurons- We have characterized the Ca2+ signaling pathways in primary cultured mouse mesencephalic dopaminergic neurons and established two animal models for the study of pathogenesis of PD: an “aging” version of the well accepted MPP+-induced dopaminergic neuron degeneration mouse model and a Zn2+ and dopamine-induced striatal dopamine depletion mouse model based on our previous results. We are using the two mouse models to study the association between the physiological function of α-synuclein and the pathogenesis of PD.
SELECTED PUBLICATIONS in the past 5 years
1. Tsai PC, Huang YH, Guo YC, Wu HT, Lin KP, Tsai YS, Liao YC, Liu YT, Liu TT, Kao LS, Yet SF, Fann MJ, Soong BW, Lee YC (2014) A novel TFG mutation causes Charcot-Marie-Tooth disease type 2 and impairs TFG function. Neurology. 2014; 83(10):903-12.
2 Wang CH, Chen YF, Wu CY, Wu PC, Huang YL, Kao CH, Lin CH, Kao LS, Tsai TF Wei YH. Cisd2 modulates the differentiation and functioning of adipocytes by regulating intracellular Ca2+ homeostasis. Hum Mol Genet.2014; 23:4770–4785.
3. Soong BW , Huang YH, Tsai PC, Huang CC, Pan HC, Lu YC, Chien HJ, Liu TT, Chang MH, Lin KP, Tu PH, Kao LS, Lee YC. Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease. Am. J. Human Genet. 2013; 92: 422-430.
4. Huang CC, Yang DM, Lin CC, Kao LS. Involvement of Rab3A in vesicle priming during exocytosis: interaction with Munc13-1 and Munc18-1. Traffic 2011; 12:1356–1370.
5. Peng JY, Lin CC, Chen YJ, Kao LS , Liu YC, Chou CC, Huang YH, Chang FR, Wu YC, Tsai YS, Hsu CN. Automatic morphological subtyping reveals new roles of caspases in mitochondrial dynamics. PLoS Comput. Biol. 2011; 7:e1002212.
6. Wu PC, Fann MJ, Kao LS. Characterization of Ca2+ Signaling Pathways in Mouse Adrenal Medullary Chromaffin Cells. J. of Neurochem. 2010; 112(5):1210-1222.
7. Yang YC, Fann MJ, Chang WH, Tai LH, Jiang JH, Kao LS. Regulation of sodium-calcium exchanger activity by creatine kinase under energy-compromised conditions. Journal of Biological Chemistry. 2010; 285(36):28275-28285.
8. Li YC, Chen BM, Wu PC, Cheng TL, Kao LS, Tao MH, Lieber A, *Roffler, S.R. Cutting Edge: mechanical forces acting on T cells immobilized via the TCR complex can trigger TCR signaling. J. Immunol. 2010; 184, 5959-5963.
9. Ku TC, Kao LS, Lin CC, Tsai YS. Morphological filter improve the efficiency of automated tracking of secretory vesicles with various dynamic properties. Microsc. Res. Tech. 2009; 72, 639-649.
10. Tsai, YS, Chung IF, Simpson, J C, Lee MI, Hsiung CC, Chiu TY, Kao LS, Chiu TC, Lin CT, Lin WC, Liang SF, Lin, CC. Automated recognition system to classify subcellular protein localizations in images of different cell lines acquired by different imaging systems. Microsc. Res. Tech. 2008; 71, 305-314.
11. Wu MP, Kao LS, Liao HT, Pan CY. Reverse mode Na+/Ca2+ exchanger triggers the release of Ca2+ from intracellular Ca2+ stores in cultured rat embryonic cortical neurons. Brain Res. 2008; 1201, 41-51.
12. Chang YF, Teng HC, Cheng SY, Wang CT, Chiou SH, Kao LS, Kao FJ, Chiou A, Yang DM. Orai1–STIM1 formed store-operated Ca2+ channels (SOCs) as the molecular components needed for Pb2+ entry in living cells. Toxicology and Applied Pharmacol. 2008; 227, 430-439.
13. Pan CY, Tsai LL, Jiang JH, Chen LW, Kao LS. The co-presence of Na+/Ca2+-K+ exchanger and Na+/Ca2+ exchanger in bovine adrenal chromaffin cells. J. Neurochem. 2008; 107(3):658-67.