Headshot of Zuhang Sheng

Zu-Hang Sheng, Ph.D.

Senior Investigator
Address
Synaptic Function Section

Building 35 (PNRC), Room 2B-215
35 Convent Drive, MSC 3706
Bethesda, Maryland 20892-3706

Dr. Sheng received his Ph.D. from the University of Pennsylvania School of Medicine, where he worked with Roland Kallen and Robert Barchi in studying sodium channels. He did his postdoctoral research in the laboratory of William Catterall at the University of Washington studying 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 axonal transport of mitochondria, endosomes, lysosomes,  autophagosomes, and presynaptic cargoes, and their impact on axonal energy maintenance and cellular homeostasis, synaptic function, aging-linked axon degeneration, and CNS regeneration after brain injury and ischemia. He has used a broad range of approaches to tackle these problems, notably the development of mature neuronal cultures from adult disease mouse models and live imaging of organelle transport in in vitro and in vivo CNS systems. Dr. Sheng served associate editor of Autophagy and the editorial board of the Journal of Biological Chemistry (JBC). He currently serves as monitoring editor for the Journal of Cell Biology (JCB). Dr. Sheng was elected as an AAAS Fellow in 2016 and an ASCB fellow in 2017. Dr. Sheng received the 2021 Dr. Francisco S. Sy Award for Excellence in Mentorship at HHS.

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Mitochondria supply ATP essential for neuronal growth and function. Neurons face exceptional challenges to maintain energy supply in distal axons, synapses, and growth cones. Anchored mitochondria serve as local energy sources, and thus regulation of mitochondrial trafficking and anchoring in axons and synapses ensures that energetically active areas are adequately supplied with ATP. In addition, anchored mitochondria need to be removed as they age or become dysfunctional. Mitochondrial dysfunction and impaired transport are hallmark features of major neurodegenerative diseases. Investigations into the regulation of mitochondrial trafficking and anchoring represent an important emerging area. Our central hypothesis is that mitochondrial trafficking and distribution is tightly regulated in order to sense, integrate, and respond to changes in metabolic and growth status, synaptic activity, aging, and pathological stress. Our ongoing investigations are focused on addressing five fundamental questions: (1) how axonal mitochondria are recruited to and captured at active presynaptic terminals in sustaining prolonged synaptic activity and plasticity); (2) how mitochondrial anchoring mechanisms are turned on or off by sensing local ATP levels; (3) how energy signaling pathways enable neurons to distribute axonal mitochondria into areas where energy consumption is high during development, regeneration, and adult neurogenesis; (4) how neurons maintain and recover chronically stressed mitochondria prior to the acute activation of Parkin-mediated mitophagy under physiological and pathological conditions; and (5) how oligodendrocyte-axon trans-cellular signaling maintains axon integrity by boosting axonal mitochondrial energetics.

Lysosomes serve as degradation hubs for autophagic and endocytic components, thus maintaining degradation capacity and cellular homeostasis essential for neuronal survival and function. Endo-lysosomal trafficking delivers targeted materials to mature lysosomes for degradation. The majority of autophagic and endocytic organelles undergo long-distance retrograde transport from distal axons toward the soma, where mature lysosomes are highly enriched. To achieve effective degradation capacity in distal regions, active lysosomes are also recruited to axons under physiological and pathological conditions. Therefore, regulation of bi-directional transport of these organelles plays a critical role in the maintenance of axonal and synaptic degradation capacity. Autophagy-lysosomal dysfunction contributes to the pathogenesis of several major neurodegenerative diseases and axonal dystrophy of lysosomal storage disorders (LSDs). However, mechanistic contributions of impaired endo-lysosome trafficking and lysosomal dysfunction to disease onset and progression remain elusive. Our research program is aimed at addressing the following fundamental issues: (1) how neurons recruit mature and degradative lysosomes into distal axons to effectively eliminate distal protein aggregates and damaged organelles; (2) how chronic lysosomal dysfunction in LSDs compromises axonal delivery of lysosomes, thus leading to axonal dystrophy; (3) how impaired autophagic transport in dopaminergic neurons (DAs) contributes to PD-linked autophagic-lysosome dysfunction, axon degeneration, and DA neuron death; and (4) how aging-associated oxidation stress impairs autophagic-lysosomal distribution and function in distal axons.

The formation of new synapses and maintenance and remodeling of mature synapses require targeted delivery of newly synthesized presynaptic cargoes from the soma to synapses. We previously identified syntabulin as a kinesin-1 motor adaptor that mediates axonal transport of presynaptic cargos to synapses. Knockdown of syntabulin reduces axonal delivery of presynaptic components and impairs synaptic formation and activity-dependent synaptic remodeling. A recent genetic study of autism patients identified a de-novo syntabulin variant that abolishes its interaction with Kinesin-1. Thus, there is an urgent need to establish axonal transport and presynaptic mechanisms underlying autism-associated phenotypes. Using syntabulin cKO mice and an autism-linked syntabulin de-novo mutation, we investigate whether defective presynaptic cargo transport serves as one of the core presynaptic mechanisms underlying autism-like synaptic dysfunction and altered social interactions and communication.

These specific aims are closely interrelated, as mitochondrial transport, mitophagy, energy homeostasis, autophagy and lysosomal function, and presynaptic maintenance are highly coordinated and mechanistically linked. We have applied cutting edge live imaging assays in a multidisciplinary systems analysis of genetic mice combined with gene rescue experiments. Our syntaphilin, snapin and syntabulin mice display striking phenotypes in axonal transport of mitochondria, endosome-lysosomes, and presynaptic cargos. Pursuing these studies will advance our knowledge of fundamental processes affecting neurodevelopmental and neurodegenerative disorders, CNS regeneration and adult neurogenesis.

Xiu-Tang Cheng, MD; PhD, Staff Scientist 

Blaine Connor, PhD, Postdoc IRTA Fellow

Yifei Gao, PhD, Postdoc Fellow

Adits S Kulkarni, BA, MD-PhD Graduate Student (NIH-University of Cambridge GPP)

Sunan Li, PhD, Research Scientist 

Friday S Pandey, PhD, Postdoc Fellow

Geetika Y Patwardhan, BS, IRTA Fellow

Joseph Concepcion Roney, PhD, Postdoc IRTA Fellow

Alexandre R Sathler, BS, IRTA Fellow

Yuxiang Xie, PhD, Staff Scientist

Gui-Jing Xiong, PhD, Research Fellow

 

 

2022

Xiu-Tang Cheng, Ning Huang, and Zu-Hang Sheng. (2022). Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration.  Neuron  110, 1899-1923. PDF 

Joseph C. Roney, Xiu-Tang Cheng, and Zu-Hang Sheng. (2022). Neuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis (Review).  Journal of Cell Biology   221, 3, 2022. PDF

Sunan Li and Zu-Hang Sheng. (2022). Energy matters: presynaptic metabolism and the maintenance of synaptic transmission.  Nature Reviews Neuroscience  23, 4-22. PDF

2021

Kelly A. Chamberlain, Ning Huang (co-first author), Yuxiang Xie, Francesca LiCausi, Sunan Li, Yan Li, and Zu-Hang Sheng. (2021). Oligodendrocytes enhance axonal energy metabolism by deacetylation of mitochondrial proteins through transcellular delivery of SIRT2.  Neuron 109, 3456-3472. PDF

  • NINDS/NIH Press: Signaling from neighboring cells provides power boost within axons. PDF
  • Neuron Preview by Eva-Maria Albers: Superfood for axons: Glial exosomes boost axonal energetics by delivery of SIRT2.  Neuron  109, 3397-3400, 2021. PDF

Joseph C Roney, Sunan Li, Tamar Farfel-Becker, Ning Huang, Tao Sun, Yuxiang Xie, Xiu-Tang Cheng, Mei-Yao Lin, Frances M Platt, and Zu-Hang Sheng. (2021). Lipid-mediated impairment of axonal lysosome transport contributing to autophagic stress.  Autophagy  17, 1796-1798. PDF

Ning Huang, Sunan Li, Yuxiang Xie, Qi Han, Xiao-Ming Xu, and Zu-Hang Sheng. (2021). Reprogramming an energetic AKT-PAK5 axis boosts axon energy supply and facilitates neuron survival and regeneration after injury and ischemia.  Current Biology   31, 3098-3114. PDF

  • Current Biology | Dispatch by Twiss et al.,Neurobiology: Resetting the axon’s batteries”. PDF

Xiu-Tang Cheng and Zu-Hang Sheng. (2021). Neurobiology: A Pathogenic Tug of War.  Current Biology  31, 491–493. PDF

Joseph C Roney, Sunan Li*, Tamar Farfel-Becker*, Ning Huang, Tao Sun, Yuxiang Xie, Xiu-Tang Cheng, Mei-Yao Lin, Frances M Platt, and Zu-Hang Sheng. (2021)Lipid-mediated motor-adaptor sequestration impairs axonal lysosome delivery leading to autophagic stress and dystrophy in Niemann-Pick type C.  Developmental Cell  56, 1452-1468. PDF

  • Developmental Cell Preview by Yap and Winckler "Lysosomes to the rescue: Anterograde axonal lysosome transport and neuronal proteostasisPDF
  • Nature Reviews Molecular Cell Biology RESEARCH HIGHLIGHT "Lysosome transport interrupted".  PDF

Gui-Jing Xiong, Xiu-Tang Cheng, Tao Sun, Yuxiang Xie, Ning Huang, Sunan Li, Meo-Yao Lin, and Zu-Hang Sheng. (2021). Defective axonal transport associates with autism-like synaptic dysfunction and social behavioral traits.  Molecular Psychiatry  26, 1472-1490.  PDF

2020

Sunan Li, Gui-Jing Xiong, Ning Huang, and Zu-Hang Sheng. (2020). The crosstalk of energy sensing and mitochondrial anchoring sustains synaptic efficacy by maintaining presynaptic metabolism.  Nature Metabolism  2, 1077-1095.  PDF

  • NIH Press: "NIH scientists reveal how the brain may fuel intense neural communication"PDF
  • Science Research Highlight "Mitochondrial anchoring in synapses". PDF

Xiu-Tang Cheng and Zu-Hang Sheng. (2020). Developmental regulation of microtubule-based axonal mitochondria trafficking and anchoring in health and diseases. Developmental Neurobiology  81, 284-299  (Review). PDF

Qi Han, Yuxiang Xie, Josue D Ordaz, Andrew J Huh, Ning Huang, Wei Wu, Naikui Liu, Kelly A Chamberlain, Zu-Hang Sheng (lead corresponding), Xiao-Ming Xu (2020). Recovering energy deficits promotes CNS axonal regeneration and functional restoration after spinal cord injuryCell Metabolism  31, 623-641.  PDF

  • NIH Press: "Boosting energy levels within damaged nerves may help them heal" PDF
2019

Rajat Puri, Xiu-Tang Cheng, Mei-Yao Lin, Ning Huang, and Zu-Hang Sheng (2019). Defending stressed mitochondria: uncovering the role of MUL1 in suppressing neuronal mitophagy.  Autophagy  16, 176-178. PDF

Tamar Farfel-Becker, Joseph V. Roney, Xiu-Tang Cheng, Sunan Li, Sean R. Cuddy, and Zu-Hang Sheng. (2020). The secret life of degradative lysosomes in axons: delivery from the soma, enzymatic activity, and local autophagic clearance.  Autophagy  16, 167-168. PDF

Dinesh C Joshi, Chuan-Li Zhang, Lavanya Babujee, Jason D Vevea, Benjamin K August, Zu-Hang Sheng, Edwin R Chapman, Timothy M Gomez, Shing Yan Chiu (2019). Inappropriate Intrusion of an Axonal Mitochondrial Anchor into Dendrites Causes Neurodegeneration. Cell Reports  29, 685-696. PDF

Rajat Puri, Xiu-Tang Cheng, Mei-Yao Lin, Ning Huang, and Zu-Hang Sheng (2019). Mul1 restrains Parkin-mediated mitophagy in mature neurons by maintaining ER-mitochondrial contacts.  Nature Communications  10, 3645. PDF

Tamar Farfel-Becker, Joseph V. Roney, Xiu-Tang Cheng, Sunan Li, Sean R. Cuddy, and Zu-Hang Sheng (2019). Neuronal soma-derived degradative lysosomes are continuously delivered to distal axons to maintain local degradation capacity.  Cell Reports  28, 51-64. PDF

Kelly A. Chamberlain and Zu-Hang Sheng (2019). Mechanisms for the maintenance and regulation of axonal energy supply. Journal of Neuroscience Research 97, 897-913 (Review). PDF

2018

Xiu-Tang Cheng, Yuxiang Xie, Bing Zhou, Ning Huang, Tamar Farfel-Becker, Zu-Hang Sheng. (2018). Revisiting LAMP1 as a marker for degradative autophagy-lysosomal organelles in the nervous system.  Autophagy. 14, 1472-1474. PDF

Xiu-Tang Cheng,  Yuxiang Xie,  Bing Zhou, Ning Huang, Tamar Farfel-Becker, and Zu-Hang Sheng (2018). Characterization of LAMP1-labeled non-degradative lysosomal and endocytic compartments in nervous systems.  Journal of Cell Biology  217, 3127-3139.  PDF

  • Featured in the JCB Spotlight Article by Kulkarni and Maday “Neuronal endosomes to lysosomes: A journey to the soma”  PDF
2017

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. PDF

Zu-Hang Sheng (2017), The Interplay of Axonal Energy Homeostasis and Mitochondrial Trafficking and Anchoring. (Invited Review), Trends in Cell Biology. 27, 403-416.  PDF

2016

Bing Zhou, Panpan Yu, Mei-Yao Lin, Tao Sun, Yanmin Cheng and Zu-Hang Sheng (2016). Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits.  Journal of Cell Biology. 204, 103-119.  PDF

  • Rockefeller Press: "Mobilizing mitochondria may be key to regenerating damaged neuronsPDF
  • NATURE | RESEARCH HIGHLIGHT "Mitochondria make nerves grow".  PDF
  • The New England Journal of Medicine RESEARCH HIGHLIGHT "Mitochondrial mobility and neuronal recovery".  PDF

Natalia S. Morsci, David H. Hall, Monica Driscoll, and Zu-Hang Sheng (2016). Age-related phasic patterns of mitochondrial maintenance in adult C. elegans neuronsJournal of Neuroscience, 36, 1373-1385.  PDF

2015

Yuxiang Xie, Bing Zhou (co-first author), 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.  PDF

  • NIH Press: “Neurons’ broken machinery piles up in ALS: NIH scientists identify a transport defect in a model of familial ALS”.  PDF

Jerome Di Giovanni & Zu-Hang Sheng (2015)Regulation of synaptic activity by snapin-mediated endolysosomal transport and sorting.  The EMBO Journal, 34, 2059-2077.  PDF

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.  PDF

Mei-Yao Lin and Zu-Hang Sheng (2015). Regulation of mitochondrial transport in neurons (Review). Exp Cell Res, 334, 35-44.  PDF

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. 

2014

Zu-Hang Sheng (2014). Mitochondrial trafficking and anchoring in neurons: New insight and implications. (Invited Review), Journal of Cell Biology, 204, 1087-98.  PDF

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. PDF

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 axonsPNAS, 111, 9953-9958.  PDF

2013

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.  PDF

  • Featured in JCB by an In Focus Article: “Syntaphilin puts the brakes on axonal mitochondriaPDF

Tao Sun, Haifa Qiao (co-first author), Ping-Yue Pan, Yanming Chen, and Zu-Hang Sheng (2013)Mobile axonal mitochondria contribute to the variability of presynaptic strength.  Cell Reports.  4, 413-419. PDF

  • NIH Press "NIH researchers discover how brain cells change their tune"PDF 
2012

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.  Autophagy  8, 976-978.  PDF

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 neuronsCell Reports  2, 42-51.  PDF

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 traffickingJournal of Cell Science, 125, 4740-4750.  

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, 545-552.  PDF

Zu-Hang Sheng & Qian Cai (2012)Mitochondrial Transport in Neurons: Impact on Synaptic Homeostasis and Neurodegeneration (Invited Review). Nature Reviews Neuroscience, 13, 77-93.  PDF

2011

Qian Cai and Zu-Hang Sheng (2011). Uncovering the role of Snapin in regulating autophagy-lysosomal function. Autophagy  7, 445-447. PDF

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.

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)

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. PDF

2010

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.  PDF

  • Neuron Preview by Yuzaki:  “Snapin snaps into the dynein complex for late endosome-lysosome trafficking and autophagy".  PDF
2009

Qian Cai and Zu-Hang Sheng (2009)Moving or Stopping Mitochondria: Miro as a Traffic Cop by Sensing Calcium.  Neuron  61, 493-496.  PDF

Qian Cai and Zu-Hang Sheng (2009). Molecular Motors and Synaptic Assembly. The Neuroscientists, 15, 78-89.  PDF

Huan Ma, Qian Cai, Wenbo Lu, Zu-Hang Sheng (co-corresponding author), Sumiko Mochida (2009). KIF5B Motor Adaptor Syntabulin Maintains Synaptic Transmission in Sympathetic NeuronsJournal of Neuroscience, 29, 13019-13029

Qian Cai and Zu-Hang Sheng (2009). Mitochondrial Transport and Docking in AxonsExperimental Neurology, 218, 257-267

Ping-Yue Pan, Jin-Hua Tian, Zu-Hang Sheng (2009). Snapin facilitates the synchronization of synaptic vesicle fusion. Neuron, 61, 412-424.  PDF

Yan-Min Chen, Claudia Gerwin, and Zu-Hang Sheng (2009). Dynein Light Chain LC8 Regulates Syntaphilin-Mediated Mitochondrial Docking in AxonsJournal of Neuroscience, 29, 9429-9438

2008

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.  PDF

  • Nature Reviews Neuroscience | RESEARCH HIGHLIGHT  “Mitochondria in the dock".  PDF

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 NeuronsJournal of Neuroscience, 28, 11333-11346

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

2007

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.  PDF

Selected from 2001-2005

Qian Cai, Claudia Gerwin, and Zu-Hang Sheng (2005). Syntabulin-mediated anterograde transport of mitochondria along the neuronal processesJournal of Cell Biology, 170, 959-969.

Qingning Su*, Qian Cai* (*co-first author), 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. 

Milan G. Chheda, Uri Ashery, Pratima Thakur, Jens Rettig,and Zu-Hang Sheng (2001). PKA phosphorylation of Snapin: modulating its interaction with the SNARE complexNature Cell Biology, 3, 331-338.