Zu-Hang Sheng, Ph.D.

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 leading 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 has also served on the editorial board of Journal of Cell Biology (JCB) and Journal of Biological Chemistry (JBC) and associate editor of Autophagy. Dr. Sheng was elected to AAAS Fellow in 2016 and ASCB fellow in 2017 for his contributions to the field of axonal transport of mitochondria and endolysosomes in maintenance of neuronal homeostasis and synaptic function in health and diseases. Dr. Sheng received the 2021 Dr. Francisco S. Sy Award for Excellence in Mentorship at HHS. Dr. Sheng is also the recipient of the 2023 NIH Director’s Award for seminal contributions to the understanding of axonal mitochondrial and lysosomal transport and maintenance of bioenergetics and cellular homeostasis in synaptic transmission and neural regeneration.

Research Interests:

As Chief of the Synaptic Functions Section, Dr. Sheng's lab has published a number of important studies focused on axonal transport of mitochondria and endolysosomes in healthy and diseased neurons. The lab 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 various organelle transport. Dr. Sheng has served as a mentor for 8 graduate students (NIH joint PhD Programs), 6 HHMI-NIH research scholars, and 20 postdoctoral fellows. Eight former trainees were appointed with faculty positions in an academic setting. 

Dr. Sheng's laboratory focuses on mechanisms regulating axonal transport that is essential for the maintenance of synaptic function and axonal homeostasis. Using genetic mouse models, his group is addressing several fundamental questions: 

• how mitochondrial transport is regulated to sense changes in synaptic activity, mitochondrial integrity, axon injury and pathological stress;
• how neurons coordinate late endocytic transport and autophagy-lysosomal function to maintain cellular homeostasis and distal degradation capacity; and  
• how impaired transport contributes to synaptic dysfunction and axonal pathology in neurodegenerative diseases. 

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 (1) boosting axonal and synaptic energy metabolism and (2) enhancing autophagy-lysosomal function for efficient clearance of dysfunctional organelles and aggregated proteins that are associated with major neurodegenerative diseases. Pursuing these investigations will advance our knowledge of fundamental processes that may affect human neurological disorders.

Research Program 1: Mitochondrial transport and energy metabolism in synaptic transmission and nerve degeneration and regeneration (NS003029)

Goals and Objectives

Mitochondria are cellular power plants that generate energy in the form of ATP to power growth, survival, and function of nerve cells. Due to their extremely polarized structures with an extended long axon, nerve cells face exceptional challenges in trafficking mitochondria to and anchoring at axons and presynaptic terminals in order to maintain energy supply. Mitochondrial trafficking and anchoring depend upon action balance of motors and anchoring proteins, so that motile mitochondria can become stationary and stationary ones can be re-mobilized. Anchored mitochondria serve as local energy sources; thus, regulation of mitochondrial trafficking and anchoring is crucial to ensure that metabolically active areas such as synapses and growth cones are adequately supplied with ATP. In addition, distal mitochondria need to be removed when they are aged or damaged throughout the neuronal lifetime. Mitochondrial dysfunction accompanied with defective transport is a key hallmark of neurodegenerative diseases. Thus, mitochondrial transport and energy metabolism in distal axons and at synapses emerge as central problems in major neurodegenerative disorders. Investigations into the regulation of mitochondrial trafficking and anchoring represent an important emerging area.

In contrast to chronic and progressive neurodegeneration, brain injury and ischemia trigger acute mitochondrial damage leading to local energy crisis. Axonal survival and regeneration requires high levels of energy consumption, and acute energy crisis contributes to regeneration failure leading to permanent neurological impairments. Thus, replacing damaged mitochondria with healthy ones will accelerate energetic recovery, and thus meet increased energy demand for nerve survival and repair. These raise a fundamental question of whether anchored mitochondria upon damaged by injury can be quickly remobilized and replaced. Our current research aims to address whether mitochondrial energetic signaling is enable neurons to enhance mitochondrial transport and restore local energy supply, thus facilitating neuronal survival and regeneration and functional recovery.

Our central hypothesis is that mitochondrial trafficking and anchoring is regulated in order to sense, integrate, and respond to changes in metabolic and growth status, synaptic activity, energy availability, pathological stress, and brain injury. Specific aims are formulated to address the following fundamental questions:

• Aim 1: Elucidate mechanisms recruiting and capturing axonal mitochondria at presynaptic terminals to meet enhanced energy consumption during sustained synaptic activity,
• Aim 2: Reveal an intrinsic signaling axis in mature neurons that remobilizes damaged mitochondria by turning off the anchoring switch in response to acute brain injury and ischemia and re-distributes healthy mitochondria to support nerve regeneration,
• Aim 3: Determine how mature neurons maintain and recover stressed mitochondria prior to the activation of Parkin-mediated mitophagy under chronic pathological conditions,
• Aim 4: Determine whether recovering local mitochondrial integrity and reversing energy metabolism facilitate CNS regeneration after injury and diseases,
• Aim 5: Reveal transcellular signaling between glial cells and neurons that maintains and boosts axonal mitochondria energetic metabolism under physiological and pathological conditions.

Pursuing these investigations will elucidate important mechanisms underlying the maintenance of synaptic efficacy, nerve regeneration, and axonal mitochondrial metabolism, thus conceptually advancing knowledge of mitochondrial pathology and axonal and presynaptic energy deficits in injury and neurological disorders.

Our series of contributions to this emerging research field.

Over the past decade, systematic studies in our lab have provided mechanistic insights and conceptual advances into the regulation of axonal mitochondrial transport and anchoring and their impact on axonal energy maintenance during sustained synaptic transmission, axonal degeneration, and regeneration, as highlighted below:

1. Mitochondrial trafficking and anchoring depend up the action balance of motors and anchoring proteins, so that motile mitochondria can become stationary and stationary ones can be re-mobilized. We identified syntaphilin (SNPH) as a static anchor specific for axonal mitochondria. Deleting the snph gene in mice robustly increases axonal mitochondria transport in both in vitro and in vivo nerve systems (Kang et al., Cell 2008).
2. Mitochondria are essential for maintaining effective synaptic transmission by generating energy and sequesteringpresynaptic Ca²⁺. However, only ~33% of presynaptic terminals in the CNS retain mitochondria, and therefore sustained synaptic activity is restricted to mitochondria-containing synapses. We recently discovered a mechanistic crosstalk between presynaptic energy sensing and mitochondrial anchoring. This energy-sensitive regulation enables neurons to recruit and retain presynaptic mitochondria to maintain presynaptic energy supply, thus fine-tuning short-term synaptic plasticity and sustaining prolonged synaptic efficacy (Li et al., Nature Metabolism 2020)
3. Synaptic transmission displays a notable pulse-to-pulse variation (PPV) in synaptic strength under identical stimulation. A fundamental question remains as to what presynaptic factors account for such dynamic PPV at single bouton levels. We revealed that motile axonal mitochondria dynamically passing through presynapses contribute to the PPV by fluctuating presynaptic ATP levels (Sun et al., Cell Reports, 2013).
4. We revealed age-associated decline of axonal mitochondria maintenance in C. elegans; genetic manipulations that extend lifespan alter the mitochondrial maintenance profile (Morsci et al., JNS 2016).
5. We demonstrated that the generation of SNPH cargo vesicles from chronically stressed mitochondria ensures that neurons respond to chronic and pathological stresses, such that dysfunctional mitochondria anchored in distal axons can be remobilized and transported to the soma for degradation (Cai et al., Current Biology 2012; Lin and Cheng et al., Neuron 2017).
6. Chronic mitochondrial stress associates with major neurodegenerative diseases. Recovering stressed mitochondria and thus energy maintenance constitutes a critical step of mitochondrial quality control in early stages of neurodegeneration. We elucidated mechanisms recovering stressed mitochondria by regulating ER-mitochondrial contacts. Identifying this pathway is particularly relevant because chronic mitochondrial dysfunction and altered ER-Mito contacts have been reported in major neurodegenerative diseases (Puri et al., Nature Communications 2019).
7. We investigated a fALS-linked mouse model and provided in vitro and in vivo evidence that endolysosomal deficits augment axonal mitochondrial pathology in spinal motor neurons (Xie et al., Neuron 2015).
8. Mature CNS axons typically fail to regenerate after injury, leading to permanent neurological impairments. We showed that elevated SNPH expression in mature CNS neurons contributes to regeneration failure. Injury-induced acute mitochondrial damage, declined mitochondrial transport in mature neurons, and enhanced energy consumption collectively lead to local energy deficits in injured axons (Zhou et al., JCB 2016).
9. We further tested our energy crisis hypothesis for regeneration failure in spinal cord injury (SCI) models. We demonstrated that enhanced axonal mitochondrial transport in snph^-/- mice robustly enhanced corticospinal tract (CST) axon regeneration passing through a spinal cord lesion, accelerated regrowth of monoaminergic axons across a transection gap, and increased compensatory sprouting of uninjured CST axons. Notably, regenerating CST axons form functional synapses, transmit electrophysiological signals, and promote motor functional recovery. Thus, our study provides new mechanistic insights into intrinsic regeneration failure in the CNS and suggests that recovering local energy supply by enhancing mitochondrial transport or by boosting cellular energetics is a promising strategy to promote nerve regeneration and functional restoration after CNS injuries (Han et al., Cell Metabolism 2020).
10. We further elucidated an intrinsic energetic repair signaling axis that boosts axonal energy supply by reprogramming axonal mitochondrial signaling in response to acute injury-ischemic stress in mature neurons and adult brains. Our study reveals an axonal mitochondrial signaling axis that responds to acute injury and ischemia by remobilizing damaged mitochondria for replacement, thereby maintaining local energy supply to support CNS survival and regeneration (Huang et al., Current Biology, in press).

Research Program 2: Axonal transport of endo-lysosomal organelles and presynaptic cargos in the maintenance of axon cellular homeostasis and synaptic function (NS002946)

Goals and Objectives

Objective One: Axonal transport of autophagy-lysosomal organelles for the maintenance of distal degradation capacity and homeostasis in healthy and diseased neurons.

Neurons are highly polarized cells with an extremely long axon, and thus face exceptional challenges in maintaining distal cellular homeostasis and synaptic function. Lysosomes serve as degradation hubs for autophagic and endocytic components. Endocytic and autophagic organelles generated in distal axons are transported retrogradely to the cell body where mature lysosomes are relatively enriched. However, lysosomes are also recruited to distal axons to achieve local degradation capacity. Therefore, bi-directional transport of these degradative organelles plays a critical role in the maintenance of axonal and synaptic homeostasis and function. Autophagy-lysosomal dysfunction contributes to the pathogenesis of major neurodegenerative diseases and lysosomal storage disorders (LSDs). However, mechanistic contributions of impaired axonal trafficking and dysfunction of lysosomes to disease onset and progression remain largely elusive. Our central hypothesis is that neurons coordinate axonal bi-directional transport of autophagic-lysosomal organelles for the maintenance of distal degradative capacity; transport defects lead to autophagic stress, axonal degeneration, and synaptic dysfunction. Specific aims are formulated to address three fundamental issues: 

• Aim 1: how neurons recruit active mature lysosomes into distal axons to eliminate protein aggregates and damaged organelles;
• Aim 2: how elevated cholesterol compromises lysosomal function and trafficking in LSD neurons, thus leading to autophagic stress and axonal dystrophy; how the pharmacologic reduction of lysosomal membranous cholesterol reverses disease phenotypes; and
• Aim 3: how impaired endolysosome transport in dopaminergic neurons contributes to Parkinson’s Disease-linked axonal degeneration.

Objective Two: Axonal transport mechanisms underlying neurodevelopmental disorders.

Synapses are distantly located from the cell bod, and thus the formation of new synapses and the maintenance and remodeling of mature synapses require seamless integration of axonal transport of presynaptic cargos. Among these presynaptic components is the scaffolding protein Bassoon, which functions as an organizer of the active zone (AZ) and appears first at newly formed presynaptic terminals. Bassoon undergoes axonal transport in organelles containing multiple presynaptic components, thus ensuring assembly, formation and maintenance of presynaptic terminals. However, the fundamental question of whether impaired axonal transport contributes to presynaptic pathology inAutism Spectrum Disorders (ASDs), a group of childhood-onset neurodevelopmental disorders, remains largely unaddressed. De novo missense mutations underlie a substantial fraction of risk for developing ASDs. While postsynaptic mechanisms play an important role in the susceptibility to ASDs, it remains unknown whether altered axonal transport of presynaptic cargos, and thus reduced formation, maturation, and maintenance of presynaptic terminals, contributes to ASD-linked pathogenesis. Investigations into axonal transport mechanisms in an in vivomodel system will provide the essential information necessary to identify core presynaptic defects at the onset of ASDs.

Summary of Research

Our primary goal is to elucidate mechanisms regulating axonal transport of various membrane organelles. By employing live imaging of adult neurons from genetic mouse models combined with gene rescue experiments, we have made the following important discoveries.

(1) We revealed that snapin acts as an adaptor linking dynein motors to endo-lysosomes and drives their retrograde transport from distal axons to the soma, thus maintaining distal degradation capacity (Cai et al., Neuron 2010).

(2) We also revealed a motor-adaptor sharing model by which late endosome-loaded dynein-snapin complex drives the retrograde transport of autophagosomes upon their fusion into hybrid organelles named amphisomes, thus maintaining effective autophagic clearance in distal axons (Cheng et al., JCB 2015).

(3) We demonstrated that the endo-lysosomal pathway exerts a bipartite regulation on presynaptic activity: while endosomal transport influences synaptic vesicle (SV) pool size by shuttling them towards degradation pathways, endosomal sorting determines SV positional priming at release sites (Di Giovanni et al., EMBO J, 2015).

(4) We investigated a familial Amyotrophic Lateral Sclerosis (fALS)-linked mouse model and provided in vitro and in vivo evidence that progressive lysosomal deficits are early fALS-linked pathological events in motor neurons (Xie and Zhou et al., Neuron 2015).

(5) We provided the guidelines for labeling degradative lysosomes in in vitro and in vivo nervous systems to characterize how lysosomal distribution, trafficking, and functionality contribute to neuronal health and disease progression (Cheng et al., JCB 2018).

(6) We further demonstrated that degradative lysosomes dynamically transport to distal axons in developing and mature neurons; disrupting axonal lysosome delivery induces autophagic stress. Thus, axonal degradation capacity is maintained through the delivery of “fresh” degradative lysosomes from the lysosomal reservoir in the soma (Farfel-Becker et al., Cell Reports 2019).

(7) Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterized by lipid accumulation in endolysosomes. An early pathologic hallmark is axonal dystrophy occurring at presymptomatic stages in NPC mice. We recently demonstrated a pathological mechanism by which elevated cholesterol on NPC lysosome membranes sequesters motor-adaptor, resulting in impaired lysosome transport into axons, thus contributing to axonal autophagosome accumulation (Roney et al., Developmental Cell 2021).

(8) We identified syntabulin (STB) as a kinesin-1 adaptor that links the motor to presynaptic cargos, thus contributing to presynaptic assembly, maintanence, and plasticity (Su and Cai et al., Nature Cell Biology, 2004; Cai et al., JCB, 2005; Cai et al., Journal of Neuroscience, 2007).

(9) We also revealed that defective axonal transport impairs presynaptic formation and maintenance, thus providing one of the core presynaptic mechanisms underlying autism-like synaptic dysfunction and altered social interactions and communication (Xiong et al., Molecular Psychiatry 2020).

Lab Members

Current Members

• 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

Lab Alumni

• Qian Cai, MD, PhD
  Postdoc Fellow: 2006-2011; Awarded NIH Pathway to Independence Award (K99/R00)
  Present Position: Associate Professor with tenure, Department of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey
• Sunit Das, MD
  HHMI Fellow: 2000-2003: Awarded NINDS Competitive Fellowship, HHMI-NIH Research Scholarship Award
  Present Position: Associate Professor with tenure, Division of Neurosurgery at St. Michael's Hospital and University of Toronto,
• Jian-Sheng Kang, PhD
  Postdoc Fellow: 2004-2009
  Present Position: Professor and Head of the laboratory of Mitochondrial Function and Neurodegenerative and Metabolic Diseases , The first affiliated hospital, Zhengzhou University, China
• Milan Chheda, MD
  HHMI Fellow: 1998-1999, HHMI-NIH Research Scholarship Award
  Present Position: Associate Professor with tenure, Departments of Medicine and Neurology, Washington University in St. Louis
• Judit Boczán, MD, PhD
  Postdoc Fellow: 2001-2003
  Present Position: Professor, Department of Neurology, University of Debrecen, Hungary
• Qingning Su, PhD
  Postdoc Fellow: 1998-2003
  Present Position: Professor, Department of Biotechnology, ShenZhen University, China
• Pingyue Pan, PhD
  Graduate Student: 2005-2009 (Joint Ph.D. Program of NIH-Shanghai JiaoTong University)
  Present Position: Assistant Professor at Rutgers University Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School
• Huan Ma, PhD
  Graduate Student: 2004-2009 (Joint Ph.D. Program of NIH-Shanghai JiaoTong University)
  Present Position: Professor, Department of Physiology, Institute of Neuroscience, School of Medicine, Zhejiang University, China
• Haifa Qiao, PhD
  Postdoc Fellow: 2009-2011
  Present Position: Research Assistant Professor, Department of Biological Science, The Florida State University College of Medicine
• Miriam A. Leenders, PhD
  Postdoc Fellow: 2001-2008; Awarded NINDS Competitive Fellowship
  Present Position: Program Director of the NINDS Extramural Program, NIH
• Guifang Lao, PhD
  Postdoc Fellow: 1997-2000
  Present Position: Healthy Scientist Administrator and Program Director of the NIDA Extramural Program, NIH
• Claudia Gerwin
  Biologist: 1999-2010
  Present Position: Program Officer, Division of Veterinary Research, NIH
• Jin-Hua Tian, PhD
  Postdoc Fellow: 2000-2006; Awarded NINDS Competitive Fellowship
• Ruth Pek Sim Chia, PhD
  Postdoc Fellow: 2009-2011
  Present Position: Staff Scientist, NIA, NIH
• Shiwei Wang, PhD
  Postdoc Fellow: 2010-2012
  Present Position: Research Fellow, University of Tasmania, Australia
• Yanmin Chen, PhD
  Postdoc Fellow: 2006-2014; Awarded NINDS Competitive Fellowship
  Present Position: Senior Review Analyst, GeneDx, Maryland
• Jerome Di Giovanni, PhD
  Postdoc Fellow: 2009-2015
  Present Position: Scientist, Cofounder, Chief Operating Officer, Ignite Social Impact
• Natalia Morsci, PhD
  Postdoc Fellow: 2012-2015
  Present Position: Lecturer, Waksman Institute of Microbiology, Rutgers, the State University of New Jersey
• Karen Shih, MD
  HHMI Fellow: 2001-2002; Awarded HHMI-NIH Research Scholarship
  Present Position: Ophthalmologist, Palo Alto Medical Foundation, Sunnyvale, CA,
• Philip Zald, MD
  HHMI Fellow: 2002-2003; Awarded HHMI-NIH Research Scholarship
  Present position: Otolaryngologist, Willamette Valley Medical Center, Oregon
• Hesham M. Zakaria, MD
  HHMI Fellow: 2010-2012; Awarded HHMI-NIH Research Scholarship
  Present Position: Neurosurgeon, California Pacific Medical Center
• Jacob Zyskind
  PostBac Fellow: 2006-2008
  Present Position: Senior Program Lead, GeneDx, Maryland
• Anthony Simone
  PostBac Fellow: 2008-2010
• Matthew Davis
  PostBac Fellow: 2010-2012
  Present Position: Medical student, George Washington University Medical School.
• Li Lu, PhD
  Graduate Student: 2004-2007 (Joint Ph.D. Program of NIH-Shanghai JiaoTong University)
  Present Position: Postdoctoral Fellow at University of Calgary, Canada
• Yi-Bing Zhu, PhD
  Graduate Student: 2007-2010 (Joint Ph.D. Program of NIH-Shanghai JiaoTong University)
• Adam Knight, PhD
  Graduate Student: 2011-2015 (The Joint Ph.D. Program of NIH-Cambridge UK)
  Present Position: Founder and CBO, Neuron23, Inc.
• Bing Zhou, PhD
  Graduate Student: 2006-2010 (The Joint Ph.D. Program of NIH-Shanghai JiaoTong University) 
  Postdoc Fellow: 2011-2016
  Present Position: Professor and Principal Investigator, Baihang University, China
• Tamar Farfel-Becker, PhD
  Postdoc Fellow: 2014-2018, Awarded NINDS Competitive Fellowship
  Present Position: Scientific Analyst at aMoon Fund.
• Sean Cuddy, BS 
  PostBac Fellow: 2015-2018
  Present Position: Graduate student, Neuroscience Program of University of Virginia.
• Mei-Yao Lin, PhD
  Postdoc Fellow: 2012-2018
  Present Position: Senior Scientist at Neuron23, Inc.
• Parry Mendapara, BS 
  PostBac Fellow: 2016-2017
  Present Position: Resident in Internal Medicine at Albert Einstein College of Medicine
• Chang Chen, PhD  
  Visiting Professor: 2017-2018
  Present Position: Professor and Principal Investigator, Institute of Biophysics, Chinese Academy of Science
• Francesca LiCausi, BS 
  PostBac Fellow: 2019-2020
  Present Position: Graduate student, Neuroscience Program,  Albert Einstein College of Medicine.
• Kelly Chamberlain, PhD
  Postdoctoral Fellow: 2017-2020, Awarded NINDS Competitive Fellowship
  Present Position: Senior Manager, Pointe Advisory
• Aasma Hossain, BS  
  Post-Bac Fellow:  2019-2021
  Present Position: Medical student, University of Michigan School of Medicine
• Yuanyi Dai, BS 
  Visiting PhD Student: 2018-2021
  Present Position: PhD Student, Peking University School of Life Sciences
• Ning Huang, PhD 
  Postdoctoral Fellow: 2017-2021
  Present Position: Associate Professor with tenure and Principal Investigator, Xi’an Jiaotong University Health Science Center, China
• Tao Sun, PhD 
  Research Scientist: 2011-2022
  Present Position: Health Science Specialist, NINDS Extramural Program
• Rajat Puri, PhD 
  Research Fellow: 2012-2022, Awarded NINDS Competitive Fellowship
  Present Position: Study Director, the Jackson laboratory 

Lab News

2023

• September 30, 2023:  Dr. Zu-Hang Sheng has been selected to receive the NIH Director’s Award for his seminal contributions to the understanding of axonal mitochondrial and lysosomal transport and maintenance of bioenergetics and cellular homeostasis in synaptic transmission and neural regeneration. Such outstanding accomplishments have brought special credit and distinction to NINDS. All current and former lab members are appreciated for their dedication and contributions.
• August 8, 2023: Sunan Li was selected with honor to speak at the Symposium of Emerging Group Leaders at International Society for Neurochemistry Meeting held at Porto, Portugal. Sunan presented her unpublished work entitled “Energy matters: reprogramming synaptoenergetics attenuates bipolar disorder-linked synaptic dysfunction and behavioral abnormalities”. Congratulations to Sunan for her well received presentation.
• July 16, 2023: Xiu-Tang Cheng was selected to speak at 2^nd Fusion Mitochondrial Conference held in Lisbon, Portugal. Xiu-Tang presented her unpublished work entitled “Disorganized mitochondrial nucleoids caused by oxidative stress contribute to aging-associated chronic decline of neuronal bioenergetics”. Congratulations to Xiu-Tang for her well received presentation.

2022

• September 15, 2022: We are excited to welcome two postdoctoral fellows joining the lab, Dr. Blaine Connor was recently awarded PhD from Johns Hopkins (Rejji Kuruvilla's lab) and Dr. Hriday Pandey was recently awarded PhD from National Brain Research Center, India (Pankaj Seth's lab).
• September 1, 2022: Congratulations to Joseph Roney, who was nominated and selected to speak at ICN-2022 Young Scientist Lecture. Zu-Hang co-chaired and gave a talk at the neuronal mitochondria session.
• August 18, 2022: Our work (Li, Xiong, Huang & Sheng, Nature Metabolism, 2020) was cited as NIH Research Accomplishments "How the brain powers communication between neurons". Congratulations to Sunan and the team!
• August 8, 2022: Welcome Alex Sathler joining the Sheng lab!  Alex is an NIH Post-Baccalaureate IRTA Fellow who was well trained in Dr. Maria C Franco lab at the Department of Biochemistry, Oregon State University, where he studied the spatial distribution of the oxidized protein in tumoroids of the u87 Glioblastoma and programed confocal image deconvolution algorithm.
• August 5, 2022: Congratulations to Sunan winning the NINDS Image Contest! Sunan established a mature excitatory neuron model that was differentiated from human iPSCs induced from Bipolar Disorder patient’s fibroblasts. This is the first human iPSC-derived neuron model in the lab.
• August 5, 2022: Welcome Aditi Kulkarni joining the lab! Aditi is a new PhD/MD student through the NIH-OxCam program and was well trained in Sandy Maday’s lab at University of Pennsylvania, where she did outstanding research studying regulation of autophagy in neuronal homeostasis and neurodegeneration.
• August 1, 2022: Welcome Geetika Patwardhan joining the lab! Geetika is a Post-Baccalaureate IRTA Fellow well trained in the Fogelgren lab at University of Hawai'i Manoa, where she studied APP trafficking and autophagic-lysosomal transport. She was awarded the 2022 OVPRS Student Award for Excellence in Research at the University of Hawai'i for her exceptional accomplishments as a student researcher.
• June 10, 2022: Dr. Rajat Puri, a research fellow in the lab, recently landed an exciting career path – accepted a Study Director position leading a research team in the Jackson laboratory. Congratulations for this fantastic job. Rajat have contributed to our lab by developing ER-Mitochondrial contact research in our transport-focused lab. Wishing him all the best and success in the Jackson laboratory.
• March 25, 2022: Dr. Tao Sun, a long time research scientist and our lab manager, was recently transferred to the NINDS extramural Neurodegeneration Cluster and promoted to Health Program Specialist.  Tao made important contributions to our synaptic mitochondria research. Congratulations to Tao.

2021

• December 14, 2021: Dr. Zu-Hang Sheng receives 2021 NINDS Director's Award in Mentoring.
• December 10, 2021: NIH Record highlights MILESTONE as "NINDS’s Sheng Wins FAPAC Mentorship Award"
• December 1, 2021: The Sheng lab held the first in person lab meeting since pandemic.
• November 4, 2021: Congratulations to Ning Huang who accepted a faculty position in Xi’an Jiao-Tong University. In the past  four years postdoc research in the Sheng lab, Ning did impressively productive research and published two first-author papers (Current Biology, Neuron) and six co-author papers. We wish Ning the best in setting up his own laboratory and developing independent research career in China..
• October 19, 2021: Dr. Zu-Hang Sheng receives the 2021 Dr. Francisco S. Sy Award for Excellence in Mentorship at HHS. This award is in recognition of Dr. Sheng’s exceptional mentorship to others from the Asian American/Native Hawaiian/Pacific Islander (AANHPI) community, fostering their professional growth and career development.
• October 13, 2021: Our review article entitled "Energy matters: presynaptic metabolism and the maintenance of synaptic transmission" by Sunan Li and Zu-Hang Sheng is accepted for publication at Nature Reviews Neuroscience.  Congratulations to Sunan! Hope the article makes contributions to this emerging field.
• August 12, 2021: Our Neuron paper was officially accepted for publication. Congratulations to Kelly, Ning and all coauthors.
• July 26, 2021: Congratulations to Joseph Roney for been selected Gregory Paul Lenardo Basic Science Award For Discoveries in Cellular and Molecular Biology. This award recognizes Joseph's  discoveries of fundamental cellular, molecular, or genetic processes using model systems that advance scientific understanding of biological processes in higher organisms.
• April 29, 2021: Ning's paper on "Reprogramming  an energetic  AKT-PAK5 axis boosts axon  energy supply and facilitates neuron survival and regeneration after injury and ischemia" was accepted for publication in Current Biology. Congratulations to Ning and all authors!
• March 28, 2021: Joseph's paper was accepted for publication at Developmental Cell. Congratulations to Joseph and all authors!
• February 4, 2021: Congratulations to Joseph Roney for being awarded PhD by the University of Oxford, through the joint NIH-Cambridge-Oxford Program.  

2020

• 2020. Lab Research was selected to the 2020 NIH Research Accomplishments - How the brain powers communication between neurons.

2018-2019

• May 17, 2019: Bing Zhou accepted a faculty position and set up his new lab in Beijing . Congratulations to Bing and good luck in the transition into a professor position.

2017

• 2017. Lab Research was selected to the 2017 NIH Research Accomplishments - Mitochondria power neuronal axon growth and regeneration.
• November 14, 2017: Dr. Sheng was elected to ASCB Fellows. ASCB Fellows are recognized for their meritorious efforts to advance cell biology and its applications and for their service to ASCB.
• May 15, 2017: Mei-Yao Lin was selected to give an oral presentation of her recent Neuron work in the NINDS retreat on June 2, 2017.
• May 9, 2017 : Dr. Sheng delivered a keynote speech at the NIH Symposium of Protein Trafficking.
• May 9, 2017: Parry was accepted to the Feinberg School of Medicine at Northwestern University with a generous financial aid package. Congratulations to Parry!
• April 4, 2017: Tao Sun was awarded the Distinguished Achievement Award from Kelly Government Solutions. This is her second time to be awarded. Congratulations to Tao!
• April 3, 2017: Mei-Yao Lin and Xiu-Tang Cheng’s paper was accepted by Neuron. Congratulations to both and other co-authors!
• April 1, 2017 : Ning Huang joined the lab as a Postdoctoral Fellow, Welcome Ning!
• February 23, 2017: Xiu-Tang Cheng was awarded NIH Outstanding Graduate Research Award, and Joseph Roney was awarded NIH Graduate Student Research Award-New Proposal. Congratulations to Xiu-Tang and Joseph!
• January 3, 2017: Kelly Chamberlain joined the lab as a Postdoctoral Fellow. Welcome Kelly! 

2016

• December 7, 2016: Dr. Sheng was appointed as an Associate Editor of Autophagy.
• November 21, 2016 : Dr. Sheng was elected to AAAS Fellow for his distinguished contributions to the field of axonal transport of mitochondria, endosomes, autophagosomes, and lysosomes in maintenance of neuronal homeostasis and synaptic function in health and diseases.
• November 12 2016: At 2016 SfN meeting held in San Diego Dr. Sheng presents a symposium talk on "Axonal transport essential for autophagy-lysosomal function in health and neurodegenerative diseases".
• August 1, 2016: Joseph Roney joined the lab as a PhD student of NIH Oxford-Cambridge Scholars Program. Welcome Joseph!
• July 11, 2016 : Parry Mendapara (from Rutgers) joined the lab as an NIH IRTA PostBac Fellow. Welcome Parry!
• July 1, 2016: Xiu-Tang Cheng was awarded the title of "Shanghai Outstanding Graduate Student”, Xiu-Tang, you deserve it! Congratulations.
• June 7, 2016 : Bing Zhou’s study on mitochondrial transport in facilitating axon regeneration is published in JCB. Congratulations to Bing!
• April 25, 201 : Dr. Sheng delivered a Keynote Speech at 6th World Congress of Molecular & Cell Biology held in Dalian, China.
• April 21, 2016: Xiu-Tang Cheng successfully passed PHD thesis defense. Congratulations for a new PhD through the NIH Joint Program with SJTU!
• April 20, 2016: Tao Sun was awarded the Distinguished Achievement Award from Kelly Government Solutions. Congratulations to Tao!
• March 22, 2016: Sheng lab new webpage is formally posted online. Thanks Sunan and her husband Yang in designing these fantastic pages!

2015

• Dec 7, 2015: Tamar Farfel-Becker was awarded the NINDS Intramural Competitive Fellowship Award. Congratulations to Tamar!
• Sept 30, 2015: Dr. Sheng was invited to join JCB Editorial Board.

Lab Resources

Access to two super-resolution microscopes: Leica SP5 and Leica TCS SP8 STED 3X at NINDS Light Imaging Facility.

The Proteins/Peptides Sequencing Facility provides amino acid sequencing of purified proteins/peptides for NINDS investigators. The facility is also available for collaborations involving protein/peptide purification and more complicated sequencing strategies.

The Flow Cytometry Core Facility provides technical, collaborative and new application research and development support to NINDS and other intramural investigators in both basic and clinical research programs requiring the use of high-throughput conventional and imaging flow cytometry, preparative fluorescence-activated cell sorting and multi-parametric in situ cytometric imaging. The Facility provides high-throughput screening of cells and assaying of their specific biological properties using appropriate biomarkers linked to fluorescent endpoints, in addition to preparative sorting of purified cell populations and/or subpopulations of interest, based on one or more cellular/subcellular parameters, as specified by the investigator.

The Light Imaging Facility provides intramural scientists with access to state-of-the-art light imaging equipment and expertise in light imaging techniques. The Facility offers training and assistance in a variety of light microscopic techniques including laser scanning confocal microscopy, video microscopy and digital image analysis. A digital image printer and slide maker are available for preparing illustrations for presentations and publications.

The Electron Microscopy (EM) Facility provides intramural NINDS investigators with the opportunity to use electron microscopic techniques in their research programs. The Facility provides assistance in all aspects of electron microscopy including project planning, specimen preparation and training.

Join Our Lab

Postdoctoral Fellowship

Axonal transport of mitochondria and lysosomes and maintenance of energy metabolism in neuronal degeneration and regeneration.

Postdoctoral positions are available to study mechanisms (1) regulating axonal mitochondrial trafficking and anchoring in order to sense, integrate, and respond to changes in metabolic and growth status, synaptic activity, energy availability, pathological stress and regeneration following brain injury; (2) regulating axonal transport of endolysosomes and autophagosomes in maintaining synaptic and axonal degradation capacity in neurodegenerative diseases; and (3) regulating glial-axon transcellular signaling in maintaining axonal integrity and energy metabolism.

Dr. Sheng’s laboratory is located in the Porter Neuroscience Research Center on the Bethesda campus of NIH, close to Washington DC. This Center is home to more than 80 research groups and more than 800 scientists from different NIH Institutes focusing on diverse aspects of neuroscience, including the cell biology of the neuron. NINDS fellows enjoy an extensive training and support infrastructure with numerous career development opportunities and broad access to the resources of NIH. For information, visit Postdoc Fellows.

The Sheng lab has applied cutting-edge microfluidic chamber technology and live and STED super-resolution imaging of mature neurons isolated from aged disease mice and human iPSC neurons, combined with in vivo analyses of genetic mouse models with gene rescue. The recent research in the Sheng lab has provided new mechanistic insights into (1) presynaptic energy-dependent variability and reliability of synaptic transmission; (2) mitochondrial transport and energy metabolism in facilitating CNS regeneration after injury; (3) axonal mitochondrial anchoring and energy maintenance in aging neurons; (4) autophagy-lysosome transport in the maintenance of axonal degradation capacity; and (5) defective axonal transport of presynaptic cargoes underlying synaptic dysfunction and behavioral abnormalities that bear similarities to autism. Recent publications from the lab include Cell (2008); Cell Metabolism (2020); Cell Reports (2012, 2013; 2019); Current Biology (2012; 2021); Developmental Cell (2021), EMBO J (2015); JCB (2005; 2013; 2014; 2015; 2016; 2018); Molecular Psychiatry (2021); Nature Cell Biology (2001; 2004); Nature Communications (2019); Neuron (2000; 2009; 2010; 2015; 2017; 2021); Nature Metabolism (2020).

The lab is equipped with two confocal microscopes (Zeiss LSM880 Airyscan and Olympus FV1000 with TIRF), a Nikon Ti-E motorized inverted stereo microscopy with Neurolucida, one electrophysiological setup, and a Seahorse XFe96 Analyzer for energy metabolic study. The lab has access to STED super-resolution microscopy, electron microscope (1200EX JEOL), and state-of-the-art mass spectrometry facility. The open lab space in Porter Neuroscience Building and extensive infrastructural core facility create an interactive environment. NIH and NINDS provides ample training opportunities for fellow career development.

The Sheng lab is a highly collegial and collaborative environment consisting of postdocs and graduate students who have the freedom to pursue a broad range of projects in the areas. Postdoctoral fellows are expected to develop a research program that will provide the foundation for a future independent research career. Positions are fully funded by the NINDS intramural program, but the trainees are encouraged to apply for independent career development funding. Former trainees in the Sheng lab have been awarded NIH K99, HHMI fellowship, and NINDS Competitive Fellowships. Ten of trainees from the Sheng lab have landed academic positions.

Qualifications:

The positions are open to highly motivated, independent, and career-oriented candidates with PhD and/or MD degrees, and less than 5 years of postdoctoral experience. Experience with one of following research areas, including neuronal organelle transport, membrane trafficking, energy metabolism, mitochondria or lysosome biology, synaptic function, neural regeneration, and aging-associated degeneration, is strongly preferred. Good written and oral communication skills are also essential. 

To apply, please send CV, research interest statement, and the name of three referees via email to:

Dr. Zu-Hang Sheng, Senior Investigator, NINDS, NIH

Publications

2024

Gui-Jing Xiong and Zu-Hang Sheng (2024). Presynaptic perspective: Axonal transport defects in neurodevelopmental disorders. Journal of Cell Biology 233 (6). 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

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

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

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

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

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

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

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

• Featured in JCB by an In Focus Article: “Syntaphilin puts the brakes on axonal mitochondria".  PDF

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

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

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

• Nature Cell Biology Cover Article featured by a News & Views article: “Hauling t-SNAREs on the microtubule highway”

Highlights

Lab Research Highlighted in NIH Press and Journals

• 2021. Neuron | Preview by Eva-Maria Albers: Superfood for axons: Glial exosomes boost axonal energetics by delivery of SIRT2. Neuron 109, 3397-3400, 2021.
• 2021. NINDS/NIH Press: Signaling from neighboring cells provides power boost within axons
• 2021. Current Biology | Dispatch Article by Twiss et al., “Neurobiology: Resetting the axon’s batteries”.
• 2021. Developmental Cell | Preview Article by Yap and Winckler  "Lysosomes to the rescue: Anterograde axonal lysosome transport and neuronal proteostasis"
• 2021. Nature Reviews Molecular Cell Biology | RESEARCH HIGHLIGHT "Lysosome transport interrupted".
• 2020. Lab Research was selected to the 2020 NIH Research Accomplishments - How the brain powers communication between neurons.
• 2020. NIH Press: NIH scientists reveal how the brain may fuel intense neural communication.
• 2020. SCIENCE | RESEARCH HIGHLIGHT "Mitochondrial anchoring in synapses"
• 2020. NIH Press: Boosting energy levels within damaged nerves may help them heal.
• 2018. JCB Spotlight Article “Neuronal endosomes to lysosomes: A journey to the soma”  
• 2017. Lab Research was selected to the 2017 NIH Research Accomplishments - Mitochondria power neuronal axon growth and regeneration.
• 2016. Rockefeller Press: Mobilizing mitochondria may be key to regenerating damaged neurons
• 2016. NATURE | RESEARCH HIGHLIGHT: Mitochondria make nerves grow.    
• 2016. The New England Journal of Medicine | RESEARCH HIGHLIGHT: Mitochondrial mobility and neuronal recovery.
• 2015. NIH Press: Neurons’ broken machinery piles up in ALS: NIH scientists identify a transport defect in a model of familial ALS
• 2013. JCB | Focus Article: “Syntaphilin puts the brakes on axonal mitochondria".
• 2013. NIH Press: NIH researchers discover how brain cells change their tune.
• 2010. Neuron | Preview Article “Snapin snaps into the dynein complex for late endosome-lysosome trafficking and autophagy".
• 2008. Nature Reviews Neuroscience | RESEARCH HIGHLIGHTS “Mitochondria in the dock".
• 2004. Nature Cell Biology | News & Views article: “Hauling t-SNAREs on the microtubule highway”.