Specific Aim 1. Mechanisms of Synchronized Synaptic Vesicle Release. Information coding in the brain depends on the timing of action potentials, which is influenced by integration of unitary excitatory inputs. The size and shape of excitatory postsynaptic currents (EPSCs) are two decisive factors in tuning the temporal and spatial precision of spiking and can be modulated by the SV fusion process. Our recent studies using the snapin-deficient cortical neurons combined with gene rescue experiments revealed a crucial role for Snapin in enhancing the efficacy of SV priming and in fine-tuning the precision of synchronous release by directly binding to synaptotagmin I (Pan et al., Neuron 2009). Snapin mutant neurons exhibit EPSCs with multiple peaks and fail to follow sustained firing under high-frequency stimulation. Re-introducing snapin into the mutant presynaptic neurons effectively accelerates EPSC kinetics by boosting the synchronicity of SV fusion. Thus, our studies reveal the role of Snapin as a unique synchronizer of SV fusion at central synapses. Several groups have independently reported an interaction between Snapin and dysbindin (BTNBP1)the product of a susceptibility gene found among the common genetic variations associated with schizophrenia. Our future studies aimed at (1) elucidating mechanisms of synchronized synaptic transmission;(2) determining whether Snapin acts in parallel or in a coordinated manner with other known priming proteins;and (3) evaluating Snapins role in the cognitive impairment prominent in schizophrenia.
Specific Aim 2. Axonal Transport of Presynaptic Cargoes Essential for Synaptic Plasticity. The formation of new synapses and remodeling of existing synapses play an important role in the various forms of synaptic plasticity and require the targeted delivery of newly synthesized synaptic components from the trans-Golgi network (TGN) in the soma to the synaptic terminals. Thus, efficient axonal transport of these newly synthesized components to nascent presynaptic boutons is critical in response to neuronal activity. Substantial evidence suggests that AZ precursor carriers are generated from TGN and traverse the developing axon to nascent synapses. Cargo vesicles must attach to their transport motors with a high degree of specificity to preserve cargo identity and targeted trafficking. However, the molecular identities of the motor-adaptor complex essential for assembling presynaptic terminals in developing neurons and in remodeling synapses of mature neurons in response to neuronal activity remain unknown. Our previous studies established that syntabulin is a motor adaptor capable of joining KIF5B and syntaxin-1 and enables syntaxin-1 transport to neuronal processes (Su et al., Nature Cell Biology, 2004). Using time-lapse imaging in live hippocampal neurons, we further demonstrate that the transport complex of syntaxin-1-syntabulin-KIF5B mediates axonal transport of the AZ components essential for presynaptic assembly. Syntabulin loss-of-function blocks formation of new presynaptic boutons during activity-dependent synaptic plasticity in developing neurons (Cai et al., J Neuroscience 2007). Our studies establish that kinesin-mediated and MT-based anterograde axonal transport is another critical factor in the cellular mechanism underlying activity-dependent presynaptic plasticity. Our recent study further demonstrated the critical role of syntabulin-mediated axonal transport in the maintenance of presynaptic function and regulation of synaptic plasticity in well-matured sympathetic SCG neurons in culture (Ma et al., J Neuroscience 2009). Our findings provide a molecular basis for future studies aimed at (1) determining whether the motor-adaptor complex regulates the transport rate in response to synaptic activity;(2) identifying the sorting signals for the axon-targeted delivery of the AZ cargo.
Specific Aim 3. Regulation of Retrograde Transport and Autophagy-Lysosomal Function. Maintaining cellular homeostasis in neurons depends on efficient intracellular transport. Late endocytic trafficking, which delivers target materials into lysosomes, is critical for maintaining efficient degradation capacities via autophagy-lysosomal pathways. An impaired autophagy-lysosomal system has been associated with the pathogenesis of neurodegenerative diseases. However, the mechanisms regulating the autophagy-lysosomal system in neurons remain incompletely understood. Dynein-mediated retrograde transport can enhance late endocytic trafficking by driving late endosomes and lysosomes close enough to fuse with higher efficiency, thus ensuring proper autophagy-lysosomal function. However, the mechanisms of coordinating these dynamic cellular processes remain unclear. In addition to its association with SVs, Snapin is present in cytosol and membrane-associated fractions in neuronal and non-neuronal cells and is co-purified with late endocytic organelles. Our recent study uncovered a critical role for Snapin in regulating late endocytic transport and membrane trafficking (Cai et al., Neuron in press). Snapin acts as a motor adaptor by attaching dynein to late endosomes. Snapin (-/-) neurons exhibit aberrant accumulation of immature lysosomes, impaired retrograde transport of late endosomes along processes, reduced lysosomal proteolysis, and impaired clearance of autolysosomes, combined with reduced neuron viability and neurodegeneration. The phenotypes are rescued by expressing the snapin transgene. Thus, our study highlights new mechanistic insights into how Snapin-dynein coordinates retrograde transport and late endosomal-lysosomal trafficking critical for autophagy-lysosomal function. Autophagy-lysosomal system is essential for quality control of intracellular components and maintenance of cellular homeostasis. Lysosomal dysfunction is one of the main cellular defects contributing to the pathogenesis of a range of neurodegenerative diseases associated with aggregation-prone intracytosolic proteins. The snapin KO mouse provides us with a unique genetic tool for characterizing the role of late endocytic transport in neurodegeneration. Papers published from the lab related to the projects: Qingning Su, Qian Cai, Claudia Gerwin, Carolyn L. Smith, Zu-Hang Sheng (2004). Nature Cell Biology 6, 941-953. Qian Cai, Claudia Gerwin, and Zu-Hang Sheng. (2005). Journal of Cell Biology 170, 959-969. Qian Cai, Pingyue Pan, and Zu-Hang Sheng. (2007). Journal of Neuroscience 27, 7284-7296. Jin-Hua Tian, Zheng-Xing Wu, Michael Unzicker, Li Lu, Qian Cai, Cuiling Li, Claudia Schirra, Ulf Matti, David Stevens, Chuxia Deng, Jens Rettig, and Zu-Hang Sheng (2005). Journal of Neuroscience 25, 10546-10555. Ping-Yue Pan, Jin-Hua Tian and Zu-Hang Sheng (2009). Neuron 61, 412-424. Qian Cai, Zu-Hang Sheng (2009). Neuroscientist 15, 78-89. Qian Cai, Li Lu, Jin-Hua Tian, Yi-Bing Zhu, Haifa Qiao, and Zu-Hang Sheng (2010). Neuron (in press).

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Cheng, Xiu-Tang; Xie, Yu-Xiang; Zhou, Bing et al. (2018) Characterization of LAMP1-labeled nondegradative lysosomal and endocytic compartments in neurons. J Cell Biol 217:3127-3139
Cheng, Xiu-Tang; Xie, Yu-Xiang; Zhou, Bing et al. (2018) Revisiting LAMP1 as a marker for degradative autophagy-lysosomal organelles in the nervous system. Autophagy 14:1472-1474
Lin, Mei-Yao; Cheng, Xiu-Tang; Tammineni, Prasad et al. (2017) Releasing Syntaphilin Removes Stressed Mitochondria from Axons Independent of Mitophagy under Pathophysiological Conditions. Neuron 94:595-610.e6
Lin, Mei-Yao; Cheng, Xiu-Tang; Xie, Yuxiang et al. (2017) Removing dysfunctional mitochondria from axons independent of mitophagy under pathophysiological conditions. Autophagy 13:1792-1794
Sheng, Zu-Hang (2017) The Interplay of Axonal Energy Homeostasis and Mitochondrial Trafficking and Anchoring. Trends Cell Biol 27:403-416
Morsci, Natalia S; Hall, David H; Driscoll, Monica et al. (2016) Age-Related Phasic Patterns of Mitochondrial Maintenance in Adult Caenorhabditis elegans Neurons. J Neurosci 36:1373-85
Zhou, Bing; Yu, Panpan; Lin, Mei-Yao et al. (2016) Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits. J Cell Biol 214:103-19
Cheng, Xiu-Tang; Zhou, Bing; Lin, Mei-Yao et al. (2015) Axonal autophagosomes use the ride-on service for retrograde transport toward the soma. Autophagy 11:1434-6
Xie, Yuxiang; Zhou, Bing; Lin, Mei-Yao et al. (2015) Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice. Neuron 87:355-70
Cheng, Xiu-Tang; Zhou, Bing; Lin, Mei-Yao et al. (2015) Axonal autophagosomes recruit dynein for retrograde transport through fusion with late endosomes. J Cell Biol 209:377-86

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