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Senior Investigator

Zu-Hang Sheng, Ph.D.

Synaptic Function Section

Porter Neuroscience Research Center
Building 35 Room 2B-215
35 Convent Drive MSC 3706
Bethesda MD 20892-3706
Office: (301) 435-4596
Lab: (301) 451-9669
Fax: (301) 480-5763
shengz@ninds.nih.gov

Dr. Sheng received his Ph.D. degree from the University of Pennsylvania, where he worked with Roland Kallen and Robert Barchi in cloning skeletal muscle sodium channel genes and studying their regulatory expression. He did his postdoctoral research in the laboratory of William Catterall at the University of Washington studying structural and functional coupling of presynaptic calcium channels and the synaptic vesicle docking/fusion machinery. Dr. Sheng joined NINDS as an investigator in 1996 and is now a senior investigator and Chief of the Synaptic Function Section. Dr. Sheng's laboratory focuses on the mechanisms regulating axonal transport of mitochondria, endocytic organelles, and synaptic cargo and their impact on axonal homeostasis, synaptic function and neurodegeneration. He has used a broad range of approaches to tackle these problems, notably the development of neuronal cultures from adult disease mouse models and live imaging of organelle transport. Dr. Sheng also serves as monitoring editor for the Journal of Cell Biology and associate editor for Autophagy and sits on the editorial board of the Journal of Biological Chemistry. Dr. Sheng was elected as an AAAS Fellow in 2016 and an ASCB fellow in 2017.

Proper neuronal function requires integration of the transport of synaptic components and the assembly and regulation of synaptic structures and function. Neurons also require specialized mechanisms to transport mitochondria to axons and retain them in the vicinity of synaptic terminals where energy production and calcium homeostasis are in high demand. Synaptic structure and function undergo activity-dependent remodeling, thereby altering axonal transport. In addition, neurons maintain cellular homeostasis through the retrograde transport of late endocytic organelles to the cell body. Maintaining efficient degradation capacities in the autophagy-lysosomal system is essential for quality control of intracellular components. Dysfunction and altered transport of mitochondria, and defective autophagy-lysosomal function have been implicated in the pathogenesis of several major neurodegenerative diseases. 

Our research goal is to elucidate the mechanisms regulating organelle transport and membrane trafficking and their impact on synaptic function, energy homeostasis, and axonal degeneration.Using genetic mouse models, we are addressing several fundamental questions: (1) how mitochondrial transport is regulated to sense changes in synaptic activity, mitochondrial integrity, axon injury, energy deficits, and pathological stress; (2) how neurons coordinate late endocytic transport and autophagy-lysosomal function to maintain cellular homeostasis; (3) how impaired transport contributes to synaptic dysfunction and axonal pathology. These studies have led to the identification of three motor adaptor and anchoring proteins (syntaphilin, snapin, and syntabulin) that regulate axonal transport of mitochondria, endo-lysosomes, autophagosomes, and synaptic cargoes. The long-term goal of the laboratory is to decipher mechanisms enhancing autophagy-lysosomal function for efficient clearance of dysfunctional mitochondria and aggregated proteins that are associated with major neurodegenerative diseases.To address these issues, we have combined molecular and cellular approaches, and live-cell imaging with a multidisciplinary systems analysis of genetically engineered mice. Pursuing these investigations will advance our knowledge of fundamental processes that may affect human neurological disorders.

Staff Image
  • Kelly Chamberlain, Ph.D.
    Postdoctoral IRTA Fellow
    301-451-2891

  • Chang Chen, Ph.D.
    Visiting Professor

  • Xiu-Tang Cheng, M.D., Ph.D.
    Research Fellow

  • Sean Cuddy, B.Sc.
    Post baccalaureate IRTA Fellow

  • Tamar Farfel-Becker, Ph.D.
    Postdoctoral Fellow

  • Ning Huang, Ph.D.
    Postdoctoral Fellow

  • Sunan Li, Ph.D.
    Postdoctoral Fellow

  • Ze-Zhi Li, M.D., Ph.D.
    Visiting Fellow

  • Mei-Yao Lin, Ph.D.
    Research Fellow

  • Rajat Puri, Ph.D.
    Research Fellow

  • Joseph Roney, B.Sc.
    Graduate Student/IRTA Fellow
    301-496-5118

  • Tao Sun, Ph.D.
    Research Scientist
    (301) 435-8131

  • Yu-Xiang Xie, Ph.D.
    Staff Scientist

  • Gui-Jing Xiong, Ph.D.
    Postdoctoral Fellow

  • 1) Xiu-Tang Cheng, Yuxiang Xie, Bing Zhou, Ning Huang, Tamar Farfel-Becker, Zu-Hang Sheng. (2018)
  • Characterization of LAMP1-labeled nondegradative lysosomal and endocytic compartments in neurons.
  • Journal of Cell Biology, Epub ahead of print
  • 2) Mei-Yao Lin, Xiu-Tang Cheng (Co-First Author), Prasad Tammineni, Yuxiang Xie, Bing Zhou, Qian Cai, Zu-Hang Sheng (2017)
  • Releasing syntaphilin removes stressed mitochondria from axons independent of mitophagy under pathophysiological conditions.
  • Neuron, 94, 595-610
  • 3) Zu-Hang Sheng (2017)
  • The Interplay of Axonal Energy Homeostasis and Mitochondrial Trafficking and Anchoring (invited review)
  • Trends in Cell Biology
  • 4) Bing Zhou, Panpan Yu, Mei-Yao Lin, Tao Sun, Yanmin Chen, and Zu-Hang Sheng (2016)
  • Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits.
  • Journal of Cell Biology, 214, 103-119. Nature News: http://www.nature.com/nature
  • 5) Natalia S. Morsci, David H. Hall, Monica Driscoll, and Zu-Hang Sheng (2016)
  • Age-Related Phasic Patterns of Mitochondrial Maintenance in Adult Caenorhabditis elegans Neurons
  • Journal of Neuroscience, 36, 1373-1385
  • 6) Yuxiang Xie, Bing Zhou, Mei-Yao Lin, Shiwei Wang, Kevin D. Foust, and Zu-Hang Sheng (2015)
  • Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice.
  • Neuron, 87, 355-370
  • 7) Jerome Di Giovanni & Zu-Hang Sheng (2015)
  • Regulation of synaptic activity by snapin-mediated endolysosomal transport and sorting.
  • The EMBO Journal
  • 8) Xiu-Tang Cheng, Bing Zhou, Mei-Yao Lin, Qian Cai, and Zu-Hang Sheng (2015)
  • Axonal autophagosomes recruit dynein for retrograde transport. through fusion with late endosomes
  • Journal of Cell Biology, 209, 377-386
  • 9) Zu-Hang Sheng (2014)
  • Mitochondrial trafficking and anchoring in neurons: New insight and implications. (Invited Review)
  • Journal of Cell Biology, 204, 1087-98
  • 10) Yanmin Chen and Zu-Hang Sheng (2013)
  • Kinesin-1�syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport.
  • Journal of Cell Biology, 202, 351-364 (Also see "In Focus" article by Ben Short)
  • 11) Tao Sun, Haifa Qiao, Ping-Yue Pan, Yanming Chen, and Zu-Hang Sheng (2013)
  • Mobile axonal mitochondria contribute to the variability of presynaptic strength.
  • Cell Reports, (see Video Summary: http://cellreports.cell.com
  • 12) Qian Cai, Hesham Mostafa Zakaria, Anthony Simone, and Zu-Hang Sheng (2012)
  • Spatial Parkin Translocation and Degradation of Depolarized Mitochondria via Mitophagy in Live Cortical Neurons.
  • Current Biology, 22
  • 13) Zu-Hang Sheng & Qian Cai (2012)
  • Mitochondrial Transport in Neurons: Impact on Synaptic Homeostasis and Neurodegeneration (Invited Review).
  • Nature Reviews Neuroscience, 13, 77-93
  • 14) Qian Cai, Li Lu, Jin-Hua Tian, Yi-Bing Zhu, Haifa Qiao, and Zu-Hang Sheng (2010)
  • Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons.
  • Neuron, 68, 73-86, (Also see Preview by M. Yuzaki)
  • 15) Qian Cai and Zu-Hang Sheng (2009)
  • Moving or Stopping Mitochondria: Miro as a Traffic Cop by Sensing Calcium (Previews).
  • Neuron, 61, 493-496
  • 16) Ping-Yue Pan, Jin-Hua Tian, Zu-Hang Sheng (2009)
  • Snapin facilitates the synchronization of synaptic vesicle fusion.
  • Neuron, 61, 412-424
  • 17) Jian-Sheng Kang, Jin-Hua Tian*, Ping-Yue Pan*, Philip Zald, Cuiling Li, Chuxia Deng, and Zu-Hang Sheng (2008)
  • Docking of Axonal Mitochondria by Syntaphilin Controls their Mobility and Affects Short-term Facilitation (*equal contribution)
  • Cell, 132, 137-248
  • 18) Mei-Yao Lin, Zu-Hang Sheng (2015)
  • Regulation of mitochondrial transport in neurons (Invited Review).
  • Exp Cell Res
  • 19) Dinesh C. Joshi, Chuan-Li Zhang, Tien-Min Lin, Anchal Gusain, Melissa G. Harris, Esther Tree, Yewin Yin, Connie Wu, Zu-Hang Sheng, Robert J Dempsey, Zsuzsanna Fabry, and Shing Yan Chiu (2015)
  • Deletion of Mitochondrial Anchoring Protects Dysmyelinating Shiverer: Implications for Progressive MS.
  • Journal of Neuroscience, 35, 5293-5306
  • 20) Yun J, Puri R, Yang H, Lizzio MA, Wu C, Sheng ZH, Guo M (2014)
  • MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin.
  • eLife, 3, e01958
  • 21) Nobuhiko Ohno, Hao Chiang, Don J Mahad, Grahame Kidd, Liping Liu, Richard M. Ransohoff, Zu-Hang Sheng, Hitoshi Komuro and Bruce D. Trapp (2014)
  • Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons.
  • PNAS, 111, 9953-9958
  • 22) Qian Cai, Hesham M Zakaria, and Zu-Hang Sheng (2012)
  • Long time-lapse imaging reveals unique features of PARK2/Parkin-mediated mitophagy in mature cortical neurons
  • Autophage, 8, 976-978
  • 23) Bing Zhou, Qian Cai, Yuxiang Xie, and Zu-Hang Sheng (2012)
  • Snapin recruits dynein to BDNF-TrkB signaling endosomes for retrograde axonal transport and is essential for dendrite growth of cortical neurons.
  • Cell Reports, 2, 42-51
  • 24) Kim HJ, Zhong Q, Zu-Hang Sheng, Yoshimori T, Liang C, Jung JU (2012)
  • Beclin 1-interacting autophagy protein Atg14L targets SNARE-associated protein Snapin to coordinate endocytic trafficking
  • Journal of Cell Science, 125, 4740-4750
  • 25) Qian Cai, Matthew Davis, and Zu-Hang Sheng (2011)
  • Regulation of Axonal Mitochondrial Transport and Its Impact on Synaptic Transmission
  • Neuroscience Research, 70, 9-15 (invited review article)
  • 26) Qian Cai and Zu-Hang Sheng (2011)
  • Uncovering the role of Snapin in regulating autophagy-lysosomal function
  • Autophagy, 7, 445-447
  • 27) Bing Zhou, Yi-Bing Zhu, Lin Lin, Qian Cai, and Zu-Hang Sheng (2011)
  • Snapin deficiency is associated with developmental defects of the central nervous system
  • Bioscience Reports, 31, 151-158
  • 28) Yi-Bing Zhu, Zu-Hang Sheng (2011)
  • Increased Axonal Mitochondrial Mobility Does Not Slow ALS-like Disease in Mutant SOD1 Mice
  • The Journal of Biological Chemistry, 286, 23432-23440
  • 29) Yan-Min Chen, Claudia Gerwin, and Zu-Hang Sheng (2009)
  • Dynein Light Chain LC8 Regulates Syntaphilin-Mediated Mitochondrial Docking in Axons
  • Journal of Neuroscience, 29, 9429-9438
  • 30) Qian Cai and Zu-Hang Sheng (2009)
  • Molecular Motors and Synaptic Assembly.
  • The Neuroscientists , 15, 78-89
  • 31) Huan Ma, Qian Cai, Wenbo Lu, Zu-Hang Sheng (co-corresponding author), Sumiko Mochida (2009)
  • KIF5B Motor Adaptor Syntabulin Maintains Synaptic Transmission in Sympathetic Neurons
  • Journal of Neuroscience, 29, 13019-13029
  • 32) Qian Cai and Zu-Hang Sheng (2009)
  • Mitochondrial Transport and Docking in Axons
  • Experimental Neurology, 218, 257-267
  • 33) AG Miriam Leenders, Lin Lin, Li-Dong Huang, Claudia Gerwin, Pei-Hua Lu, and Zu-Hang Sheng (2008)
  • The Role of MAP1A Light Chain 2 in Synaptic Surface Retention of Cav2.2 Channels in Hippocampal Neurons
  • Journal of Neuroscience, 28, 11333-11346
  • 34) Wenbo Lu, Huan Ma, Zu-Hang Sheng, and Sumiko Mochida. (2008)
  • Dynamin and activity regulate synaptic vesicle recycling in sympathetic neurons.
  • The Journal of Biological Chemistry, 284, 1930-1937
  • 35) Qain Cai, Ping-Yue Pan, and Zu-Hang Sheng (2007)
  • Syntabulin-kinesin-1 family 5B-mediated axonal transport contributes to activity-dependent presynaptic assembly
  • Journal of Neuroscience, 27, 7284-7296 (With Weekly Editorial News)
  • 36) Ping-Yue Pan, Qian Cai, Lin Lin, Pei-Hua Lu, Shu-Min Duan, and Zu-Hang Sheng. (2005)
  • SNAP29-mediated modulation of synaptic transmission in cultured hippocampal neurons
  • The Journal of Biological Chemistry , 280, 25769-25779
  • 37) Qian Cai, Claudia Gerwin, and Zu-Hang Sheng (2005)
  • Syntabulin-mediated anterograde transport of mitochondria along the neuronal processes
  • Journal of Cell Biology , 170, 959-969
  • 38) Jin-Hua Tian, Zheng-Xing Wu, Michael Unzicker, Li Lu, Qian Cai, Cuiling Li, Claudia Schirra, Ulf Matti, David Stevens, Chuxia Deng, Jens Rettig, and Zu-Hang Sheng (2005)
  • The Role of Snapin in Neurosecretion: Snapin Knockout Mice Exhibit Impaired Calcium-dependent Exocytosis of Large Dense-core Vesicles in Chromaffin Cells
  • Journal of Neuroscience, 25, 10546-10555 (With Weekly Editorial News)
  • 39) Xiao-Ke Chen, Lie-Cheng Wang, Yang Zhou, Qian Cai, Murali Prakriya, Kai-Lai Duan, Zu-Hang Sheng, Christopher Lingle & Zhuan Zhou (2005)
  • Activation of GPCRs modulates quantal size in chromaffin cells through Gbg
  • Nature Neuroscience, 8, 1160-1168
  • 40) Wu LJ, Leenders AG, Cooperman S, Meyron-Holtz E, Smith S, Land W, Tsai RY, Berger UV, Sheng ZH, Rouault TA (2004)
  • Expression of the iron transporter ferroportin in synaptic vesicles and the blood-brain barrier
  • Brain Res. , 1001, 108-17
  • 41) Pratima Thakur, David R. Stevens, Zu-Hang Sheng and Jens Rettig (2004)
  • Effects of PKA-mediated phosphorylation of Snapin on synaptic transmission in cultured hippocampal neurons
  • Journal of Neuroscience, 24, 6476-6481
  • 42) Qian Cai*, Qingning Su*, Claudia Gerwin, Carolyn L. Smith, Zu-Hang Sheng (2004)
  • Syntabulin: a microtubule-associated protein implicated in syntaxin trafficking in neurons
  • Nature Cell Biology, 6, 941-953 (with news & views)(*equal contributions)
  • 43) Judit Boczan, A. G. Miriam Leenders, and Zu-Hang Sheng (2004)
  • Phosphorylation of syntaphilin by PKA modulates its interaction with syntaxin-1 and annuls its inhibitory effect on vesicle exocytosis
  • The Journal of Biological Chemistry, 279, 18911-18919
  • 44) Brij B. Singh, Timothy P. Lockwich, Bidhan C. Bandyopadhyay, Xibao Liu, Sunitha Bollimuntha, So-ching Brazer, Christian Combs, Sunit Das, A.G. Miriam Leenders, Zu-Hang Sheng, Mark A. Knepper, Suresh V. Ambudkar, and Indu S. Ambudkar (2004)
  • VAMP2-Dependent Exocytosis Regulates Plasma Membrane Insertion of TRPC3 Channels and Contributes to Agonist-Stimulated Ca2+ Influx
  • Molecular Cell, 15, 635-646
  • 45) Haitao Song, Liping Nie, Adrian Rodriguez-Contreras, Zu-Hang Sheng, and Ebenexer Yamoah (2003)
  • Functional interaction of auxiliary subunits and synaptic proteins with Ca1.3 may impart hair cell Ca current properties
  • J Neurophysiol., 89, 1143
  • 46) Jin-Hua Tian, Sunit Das, and Zu-Hang Sheng (2003)
  • Ca-dependent phosphorylation of syntaxin-1A by DAP-kinase regulates its interaction with Munc-18
  • The Journal of Biological Chemistry, 278, 26265-26274
  • 47) Sunit Das, Judit Boczan, Claudia Gerwin, Philip B. Zald and Zu-Hang Sheng (2003)
  • Regional and developmental regulation of syntaphilin expression in the brain: a candidate molecular element of synaptic functional differentiation
  • Molecular Brain Research, 116, 38-49
  • 48) Sunit Das, Claudia Gerwin, and Zu-Hang Sheng (2003)
  • Syntaphilin binds to dynamin-1 and inhibits dynamin-dependent endocytosis
  • The Journal of Biological Chemistry, 278, 41221-41226
  • 49) Miriam Leenders, Arn M. J. M. van den Maagdenberg, Fernando H. Lopes da Silva, Zu-Hang Sheng, Peter C. Molenaar and Wim E.J.M. Ghijsen (2002)
  • Neurotransmitter release from tottering mice nerve terminals with reduced expression of mutated P-, Q-type Ca2+-channels
  • Eur. J. Neuroscience, 15, 13-18
  • 50) Milan G. Chheda, Uri Ashery, Pratima Thakur, Jens Rettig,and Zu-Hang Sheng (2001)
  • PKA phosphorylation of Snapin: modulating its interaction with the SNARE complex
  • Nature Cell Biology, 3, 331-338
  • 51) Qingning Su, Sumiko Mochida, Jin-Hua Tian, Rashi Mehta,and Zu-Hang Sheng (2001)
  • SNAP-29: A General SNARE Protein that Inhibits SNARE Disassembly and is Implicated in Synaptic Transmission
  • Proc. Natl. Acad. Sci. USA, 98, 1438-1443
  • 52) Guifang Lao, Volker Scheuss, Claudia M. Gerwin, Qingning Su, Sumiko Mochida, Jens Rettig, and Zu-Hang Sheng. (2000)
  • Syntaphilin: a syntaxin-1 clamp that controls SNARE assembly
  • Neuron, 25, 191-201
  • 53) Jeffrey M. Ilardi, Sumiko Mochida, and Zu-Hang Sheng (1999)
  • Snapin: a SNARE-associated protein implicated in synaptic transmission
  • Nature Neuroscience , 2, 119-124
  • 54) Lucas D. Pozzo-Miller, Wolfram Gottschalk, Li Zhang, Kathryn McDermott, Chikara Oho, Zu-Hang Sheng, and Bai Lu (1999)
  • The role of BDNF in Hippocampal synaptic plasticity: impairment in synaptic vesicle docking and synaptic protein distribution in BDNF knockout mice
  • J. Neuroscience , 19, 4972-4983
  • 55) Zu-Hang Sheng, Ruth E. Westenbroek, and William A. Catterall (1998)
  • Physical link and functional coupling of presynaptic calcium channels and synaptic vesicle docking/fusion machinery
  • J. Bioenergetics & Biomembranes , 30, 335-345
  • 56) Zu-Hang Sheng, Charles Yokoyoma, and William A. Catterall (1997)
  • Interaction of the synprint site of N-type calcium channels with the C2B domain of synaptotagmin I
  • Proc. Natl. Acad. Sci. USA , 94, 5405-5410
  • 57) Jens Rettig, Christian Heinemann, Uri Ashery, Zu-Hang Sheng, Charles T. Yokoyama, William A. Catterall, and Erwin Neher (1997)
  • Alteration of Ca2+ dependence of neurotransmitter release by disruption of Ca2+ channel/SNARE protein interaction
  • J Neuroscience , 17, 6647-6656
  • 58) Charles Yokoyama, Zu-Hang Sheng, and William A. Catterall (1997)
  • Phosphorylation of the synprint site on N-type calcium channels inhibits interactions with SNARE protein
  • J Neuroscience , 17, 6929-6938
  • 59) Sumiko Mochida, Zu-Hang Sheng, Carl Baker, Haruo Kobayashi, and William A. Catterall (1996)
  • Inhibition of neurotransmission by peptides containing the synaptic protein interaction site of N-type calcium channels
  • Neuron, 17, 781-788
  • 60) Jens Rettig, Zu-Hang Sheng, D. Kyle Kim, Connie D. Hodson, Terry P. Snutch, and William A. Catterall (1996)
  • Isoform-specific interaction of the a1A subunits of brain calcium channels with the presynaptic proteins syntaxin and SNAP-25
  • Proc. Natl. Acad. Sci. USA, 93, 7363-7368
  • 61) Zu-Hang Sheng, Jens Rettig, Terry Cook, and William A. Catterall (1996)
  • Calcium dependent interaction of neuronal N-type calcium channels with presynaptic fusion proteins
  • Nature , 379, 451-454
  • 62) Zu-Hang Sheng, Jens Rettig, Masami Takahashi, and William A. Catterall (1994)
  • Identification of a syntaxin-binding site on N-type calcium channels
  • Neuron, 13, 1303-1313
  • 63) Zu-Hang Sheng, Hui Zhang, Robert L. Barchi, and Roland G. Kallen (1994)
  • Molecular cloning and functional analysis of the promoter of rat skeletal muscle voltage-sensitive sodium channel subtype 2 (rSkM2): evidence for muscle-specific nuclear protein binding to the core promoter
  • DNA and Cell Biology , 13, 9-23
  • 64) Roland G. Kallen, Zu-Hang Sheng, Liquiong Chen, Jan Yang, Rogart, R.B., and Robert L. Barchi (1990)
  • Primary structure and differential expression of a sodium channel characteristic of immature and denervated rat skeletal muscle
  • Neuron , 4, 233-242
  • 65) Trimmer, J.S., Cooperman, S.S., Tomiko, S.A., Zhou, J., Crean, S.M., Boyle, M.B., Kallen, R.G., Zu-Hang Sheng, Barchi, R.L., Sigworth, F.J., Goodman, R.G., Agnew, S.A., and Mandel, G (1989)
  • Primary structure and functional expression of a mammalian skeletal muscle sodium channel
  • Neuron , 3, 33-49
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