Title: Disruption of adaptor protein 2μ (AP-2μ) in cochlear hair cells impairs vesicle reloading of synaptic release sites and hearing
Date/Time: December 28, 2015 – 13:40
Place: FENS G035
Abstract: Disabling hearing impairment (HI) affects 360 million people worldwide, and prevalence increases with age. So far, no causal treatment is available for its most common form which is resulted from defect in hair cell or spiral ganglion neurons, called sensorineural HI. Active zones (AZs) of inner hair cells (IHCs) indefatigably release hundreds of vesicles per second, requiring each release site to replenish vesicles at tens per second. Here, we report that the endocytic adaptor protein 2µ (AP-2µ) is required for release site replenishment and hearing. We show that hair-cell-specific disruption of AP-2µ slows IHC exocytosis immediately after fusion of the readily releasable pool of vesicles, despite normal abundance of membrane-proximal vesicles and intact endocytic membrane retrieval. Sound-driven postsynaptic spiking was reduced in a use-dependent manner and the altered interspike interval statistics suggested a slowed replenishment of release sites. Sustained strong stimulation led to accumulation of endosome-like vacuoles, fewer clathrin-coated endocytic intermediates and vesicle-depletion of the membrane-distal synaptic ribbon in AP-2µ-deficient IHCs, indicating a further role of AP-2µ in clathrin-dependent vesicle reformation on a timescale of many seconds. Finally, we characterized the interaction of AP-2 with its cargo otoferlin. We propose that binding of AP-2 to otoferlin facilitates replenishment of release sites via speeding clearance of exocytosed material, in addition to a role of AP-2 in endocytic recycling.
Bio: I was born at Seoul, Korea in 1971 and served as a soldier in the army from 1991 to 1994. I received Ph.D. in neuroscience in 2004 from Dep. of Physiology and Biophysics, Inha University, school of medicine, Korea. Research topic was “Effects of Caveolin-1 on the Na+-Ca2+ Exchanger Activity in Soma of Rat Cerebellar Purkinje Neuron” that was supervised by Chang Kook Suh. I had been trained as a postdoctoral fellow in Dep. of Life Science, Pohang University of science and technology (POSTECH), Pohang, Korea since 2005 and was promoted to research assistant professor from the same institute in 2007. In POSTECH, research topic was that synaptic adhesion protein, neuroligin-1 (synaptic adhesion molecule) affected synaptic plasticity and the fear memory in amygdala. To study on vesicle dynamics, I came to Max-Planck-Institut für Experimentelle Medizin in Germany in 2009 with Korea government supported grant. Research topic was the measurement of calcium cooperativity on vesicle release in hippocampal neurons in simple autaptic culture system. To come true my purpose, I’ve moved to Inner ear lab (present: Auditory Neuroscience Institute) in 2012. I have studied on ribbon synapse and hearing restoration in deafness mouse models with gene therapy. Selected publications In Inner ear lab (Auditory Neuroscience Institute) SangYong Jung#, Tanja Maritzen#, Carolin Wichmann#, Zhizi Jing, Andreas Neef, Natalia H. Revelo, Hanan Al-Moyed, Sandra Meese, Sonja M. Wojcik, Iliana Panou, Haydar Bulut, Peter Schu, Ralf Ficner, Ellen Reisinger, Silvio O. Rizzoli, Jakob Neef, Nicola Strenzke, Volker Haucke and Tobias Moser. (2015) Disruption of adaptor protein 2µ (AP-2µ) in cochlear hair cells impairs vesicle reloading of synaptic release sites and hearing. EMBO J, (#Equal contribution) S. Jung#, T. Oshima-Takago#, R. Chakrabarti, M.M. Picher, A.B. Wong, Z. Jing, A.-M. Oprisoreanu, F. Göttfert, S. Michanksi, F. Predoehl, K. Michel, Tina Pangršič-Vilfan, S. M. Hell, S. Schoch, N. Strenzke, C. Wichmann and T. Moser. (2015) Rab interacting molecule 2α (RIM2α) regulates CaV1.3 Ca2+ channels and synaptic vesicle tethering at hair cell active zones. Proc Natl Acad Sci U S A. (#Equal contribution) Max-Planck-Institut für Experimentelle Medizin Andrea Burgalossi, Sangyong Jung, Kwun-nok Mimi Man, Ramya Nair, Wolf J Jockusch, Sonja M Wojcik, Nils Brose& Jeong-Seop Rhee, (2012) Analysis of neurotransmitter release mechanisms by photolysis of caged Ca²⁺ in an autaptic neuron culture system. Nature Protocols Andrea Burgalossi, Sangyong Jung, Guido Meyer, Wolf J. Jockusch, Olaf Jahn, Holger Taschenberger, Vincent M. O'Connor, Tei-ichi Nishiki, Masami Takahashi, Nils Brose, Jeong-Seop Rhee, (2010) SNARE Protein Recycling by αSNAP and βSNAP Supports Synaptic Vesicle Priming. Neuron. In POSTECH Jung SY, Kim J, Kwon OB, Jung JH, An K, Jeong AY, Lee CJ, Choi YB, Bailey CH, Kandel ER, Kim JH. (2010) Input-specific synaptic plasticity in the amygdala is regulated by neuroligin-1 via postsynaptic NMDA receptors. Proc Natl Acad Sci U S A. Kim J*, Jung SY*, Lee YK, Park SK, Choi JS, Lee CJ, Kim HS, Choi YB, Scheiffele. P, Bailey C, Kandel ER, Kim JH. (2008) Neuroligin-1 is required for normal expression of LTP and associative fear memory in the amygdala of adult animals. Proc Natl Acad Sci U S A. (* Equal contribution)