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.
Aasma Hossain, BS
Xiu-Tang Cheng, MD; PhD
Sunan Li, PhD
Rajat Puri, PhD
Tao Sun, PhD
Joseph Concepcion Roney, PhD
Yuxiang Xie, PhD
Gui-Jing Xiong, PhD
Kelly Anne Chamberlain, PhD
Ning Huang, PhD
Zezhi Li, MD
Xiu-Tang Cheng, Ning Huang, and Zu-Hang Sheng. (2022). Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration. Neuron. https://authors.elsevier.com/a/1ewBi3BtfH1XnH
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 Vol. 221 No. 3 e202111077.
Sunan Li and Zu-Hang Sheng. (2022). Energy matters: presynaptic metabolism and the maintenance of synaptic transmission. Nature Reviews Neuroscience 23, 4-22.
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.
- NINDS/NIH Press: Signaling from neighboring cells provides power boost within axons.
- Neuron Preview by Eva-Maria Albers: Superfood for axons: Glial exosomes boost axonal energetics by delivery of SIRT2. Neuron 109, 3397-3400, 2021.
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.
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.
- Current Biology | Dispatch Article by Twiss et al., “Neurobiology: Resetting the axon’s batteries”.
Xiu-Tang Cheng and Zu-Hang Sheng. (2021). Neurobiology: A Pathogenic Tug of War. Current Biology 31, 491–493.
Joseph C Roney, Sunan Li*, Tamar Farfel-Becker*(*equal contributions), 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.
- Developmental Cell Preview Article by Yap and Winckler "Lysosomes to the rescue: Anterograde axonal lysosome transport and neuronal proteostasis"
- Nature Reviews Molecular Cell Biology | RESEARCH HIGHLIGHT "Lysosome transport interrupted".
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.
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.
- NIH Press: NIH scientists reveal how the brain may fuel intense neural communication.
- Science | Research Highlight "Mitochondrial anchoring in synapses".
Xiu-Tang Cheng and Zu-Hang Sheng. (2020). Developmental regulation of microtubule-based axonal mitochondria trafficking and anchoring in health and diseases. Developmental Neurobiology (doi: 10.1002/dneu.22748. Online ahead of print) (invited review).
Qi Han, Yuxiang Xie, Josue D Ordaz, Andrew J Huh, Ning Huang, Wei Wu, Naikui Liu, Kelly A Chamberlain, Zu-Hang Sheng (lead corresponding author), Xiao-Ming Xu (2020). Recovering energy deficits promotes CNS axonal regeneration and functional restoration after spinal cord injury. Cell Metabolism 31, 623-641.
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.
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.
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 (invited review).
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.
- Featured by the JCB Spotlight Article “Neuronal endosomes to lysosomes: A journey to the soma”
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.
Zu-Hang Sheng (2017), The Interplay of Axonal Energy Homeostasis and Mitochondrial Trafficking and Anchoring. (Invited Review), Trends in Cell Biology.
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.
- Rockefeller University Press: Mobilizing mitochondria may be key to regenerating damaged neurons
- NATURE | RESEARCH HIGHLIGHT: Mitochondria make nerves grow.
- The New England Journal of Medicine | RESEARCH HIGHLIGHT: Mitochondrial mobility and neuronal recovery.
Natalia S. Morsci, David H. Hall, Monica Driscoll, and Zu-Hang Sheng (2016). Age-related phasic patterns of mitochondrial maintenance in adult C. elegans neurons. Journal of Neuroscience, 36, 1373-1385.
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.
- NIH Press: “Neurons’ broken machinery piles up in ALS: NIH scientists identify a transport defect in a model of familial ALS”
Jerome Di Giovanni & Zu-Hang Sheng (2015). Regulation of synaptic activity by snapin-mediated endolysosomal transport and sorting. The EMBO Journal, 34, 2059-2077.
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.
Zu-Hang Sheng (2014), Mitochondrial trafficking and anchoring in neurons: New insight and implications. (Invited Review), Journal of Cell Biology, 204, 1087-98.
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.
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.
- Featured in JCB Focus Article: “Syntaphilin puts the brakes on axonal mitochondria.
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, (see Video Summary: http://cellreports.cell.com).
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.
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.
Zu-Hang Sheng & Qian Cai (2012). Mitochondrial Transport in Neurons: Impact on Synaptic Homeostasis and Neurodegeneration (Invited Review). Nature Reviews Neuroscience, 13, 77-93.
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.
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,
- Neuron Preview “Snapin snaps into the dynein complex for late endosome-lysosome trafficking and autophagy".
Qian Cai and Zu-Hang Sheng (2009). Moving or Stopping Mitochondria: Miro as a Traffic Cop by Sensing Calcium. Neuron, 61, 493-496.
Ping-Yue Pan, Jin-Hua Tian, Zu-Hang Sheng (2009). Snapin facilitates the synchronization of synaptic vesicle fusion. Neuron, 61, 412-424
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.
- Nature Reviews Neuroscience | RESEARCH HIGHLIGHT “Mitochondria in the dock".
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)
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.
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.
- Nature Cell Biology News & Views: “Hauling t-SNAREs on the microtubule highway”.
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.