Mitochondrial transport and energy homeostasis in synaptic transmission, neuronal degeneration and regeneration
Zuhang Sheng, PhD
Chief of the Synaptic Function Section
AAAS and ASCB Fellow
Editor for JCB, Autophagy, and JBC
Background: The research in the Sheng laboratory is focused on mechanisms regulating axonal transport in healthy and diseased neurons. By applying cutting-edge approaches, including adult neuronal cultures from aged disease models, live imaging of organelle transport, and in vivo analyses of gene rescue effects, his laboratory is addressing several fundamental questions: (1) how mitochondrial transport is regulated to sense changes in synaptic activity, mitochondrial integrity, axon injury and pathological stress; (2) how neurons coordinate late endocytic transport and autophagy-lysosomal function to maintain cellular homeostasis; (3) how synaptic activity is regulated by endo-lysosomal trafficking and sorting; (4) how presynaptic cargo transport contributes to synapse formation and remodeling; and (5) how impaired transport contributes to synaptic dysfunction and axonal pathology in neurodegenerative diseases. These studies have led to the identification of motor adaptor and anchoring proteins that regulate axonal transport of mitochondria, endo-lysosomes, and synaptic cargoes. Their studies have provided new mechanistic insights into synaptic variability, energy deficits in CNS regeneration failure, and mitochondrial maintenance in organismal aging and axonal degeneration. Their work is broadly relevant to understanding mitochondrial pathology, energy deficits, and lysosomal dysfunction in major neurodegenerative diseases.
- Su*, Q., Q. Cai*, C. Gerwin, C. L. Smith, and Z.-H. Sheng (2004). Syntabulin: a microtubule-associated protein implicated in syntaxin transport in neurons. Nature Cell Biology 6, 941-953.
- Kang, J.-S., J.-H. Tian, P. Zald, P.-Y. Pan, C. Li, C. Deng, and Z.-H. Sheng (2008). Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell 132, 137-148.
- Cai, Q., L. Lu, J.-H. Tian, Y.-B. Zhu, H. Qiao, Z.-H. Sheng (2010). Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons. Neuron 68, 73-86.
- Cai, Q., H. M. Zakaria, A. Simone, and Z.-H. Sheng (2012). Spatial Parkin Translocation and Degradation of Depolarized Mitochondria via Mitophagy in Live Cortical Neurons. Current Biology 22, 545-552.
- Sun*, T., H. Qiao*, P.-Y. Pan, Y. Chen, and Z.-H. Sheng (2013). Mobile axonal mitochondria contribute to the variability of presynaptic strength. Cell Reports4, 413-419.
- Cheng, X.-T., B. Zhou, M.-Y. Lin, and Z.-H. Sheng (2015). Axonal autophagosomes acquire dynein motors for retrograde transport through fusion with late endosomes. Journal of Cell Biology 209, 377-386.
- Xie*, Y., B. Zhou*, M.-Y. Lin, S. Wang, K. D. Foust, and Z.-H. Sheng (2015). Endolysosome deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS-linked mice. Neuron 87, 355-370.
- Di Giovanni, J, and Z.-H. Sheng (2015). Regulation of synaptic activity by snapin-mediated endolysosomal transport and sorting. EMBO Journal 34, 2059-2077.
- Zhou, B., P. Yu, M‑Y. Lin, T, Sun, Y. Chen, and Z.-H. Sheng (2016). Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits. Journal of Cell Biology 214, 203-119.
- Lin*, M-Y., X-T. Cheng*, P Tammineni, Y. Xie, B. Zhou, Q. Cai, and Z-H. Sheng (2017). Releasing syntaphilin removes stressed mitochondria from axons independent of mitophagy under pathophysiological conditions. Neuron 94, 595-610.