Zu-Hang Sheng, Ph.D.
Synaptic Function Section
Building 35, Room 2B-215
35 Convent Drive
Bethesda, MD 20892-3706
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.
Kang JS, Tian JH, Pan PY, Zald P, Li C, Deng C, Sheng ZH. Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell. 2008;132(1):137-48.
Xie Y, Zhou B, Lin MY, Wang S, Foust KD, Sheng ZH. Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice. Neuron. 2015;87(2):355-70.
Huang N, Li S, Xie Y, Han Q, Xu XM, Sheng ZH. Reprogramming an energetic AKT-PAK5 axis boosts axon energy supply and facilitates neuron survival and regeneration after injury and ischemia. Curr Biol. 2021;31(14):3098-3114.e7.
Li S, Xiong GJ, Huang N, Sheng ZH. The cross-talk of energy sensing and mitochondrial anchoring sustains synaptic efficacy by maintaining presynaptic metabolism. Nat Metab. 2020;2(10):1077-1095.
Lin MY, Cheng XT, Tammineni P, Xie Y, Zhou B, Cai Q, Sheng ZH. Releasing Syntaphilin Removes Stressed Mitochondria from Axons Independent of Mitophagy under Pathophysiological Conditions. Neuron. 2017;94(3):595-610.e6.
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This page was last updated on August 18th, 2021