Zu-hang Sheng - Academia.edu (original) (raw)

Papers by Zu-hang Sheng

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Aug 8, 2018

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Jul 14, 2021

Current Biology, May 1, 2021

Pathogenic mutations in the kinase LRRK2 have been implicated in Parkinson's disease. A new s... more Pathogenic mutations in the kinase LRRK2 have been implicated in Parkinson's disease. A new study shows that hyperactivation of this kinase reduces the processivity of autophagosomal retrograde transport in axons through an unproductive 'tug-of-war' between anterograde and retrograde motors, thus contributing to autophagy dysfunction and axonal degeneration.

Current Opinion in Neurobiology, Jun 1, 2023

The Journal of Neuroscience, Aug 15, 2022

The mitochondrial anchor syntaphilin (SNPH) is a key mitochondrial protein normally expressed in ... more The mitochondrial anchor syntaphilin (SNPH) is a key mitochondrial protein normally expressed in axons to maintain neuronal health by positioning mitochondria along axons for metabolic needs. However, in 2019 we discovered a novel form of excitotoxicity that results when SNPH is misplaced into neuronal dendrites in disease models. A key unanswered question about this SNPH excitotoxicity is the pathologic molecules that trigger misplacement or intrusion of SNPH into dendrites. Here, we identified two different classes of pathologic molecules that interact to trigger dendritic SNPH intrusion. Using primary hippocampal neuronal cultures from mice of either sex, we demonstrated that the pro-inflammatory cytokine IL-1b interacts with NMDA to trigger SNPH intrusion into dendrites. First, IL-1b and NMDA each individually triggers dendritic SNPH intrusion. Second, IL-1b and NMDA do not act independently but interact. Thus, blocking NMDAR by the antagonist MK-801 blocks IL-1b from triggering dendritic SNPH intrusion. Further, decoupling the known interaction between IL-1b and NMDAR by tyrosine inhibitors prevents either IL-1b or NMDA from triggering dendritic SNPH intrusion. Third, neuronal toxicity caused by IL-1b or NMDA is strongly ameliorated in SNPH 2/2 neurons. Together, we hypothesize that the known bipartite IL-1b/NMDAR crosstalk converges to trigger misplacement of SNPH in dendrites as a final common pathway to cause neurodegeneration. Targeting dendritic SNPH in this novel tripartite IL-1b/NMDAR/SNPH interaction could be a strategic downstream locus for ameliorating neurotoxicity in inflammatory diseases.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, May 14, 2020

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, May 15, 2017

Significance Lysosomes are found in all neuronal domains, including the soma, axon, and dendrites... more Significance Lysosomes are found in all neuronal domains, including the soma, axon, and dendrites. How neurons are transported in these domains, however, remains poorly understood. In the present study, we show that a protein ensemble comprising BORC, Arl8, SKIP, and kinesin-1 specifically drives lysosome transport into the axon and not the dendrites. We also show that this mechanism of axonal lysosome transport is essential for maintenance of growthcone dynamics and turnover of autophagosomes in the distal axon. These findings imply that transport of lysosomes into the axon and the dendrites occurs by different mechanisms, and demonstrate that BORC-regulated lysosome transport is critical for axonal functions.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Feb 9, 2017

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Jun 26, 2017

Neuron, Jun 1, 2022

Mitochondria generate ATP essential for neuronal growth, function, and regeneration. Due to their... more Mitochondria generate ATP essential for neuronal growth, function, and regeneration. Due to their polarized structures, neurons face exceptional challenges to deliver mitochondria to and maintain energy homeostasis throughout long axons and terminal branches where energy is in high demand. Chronic mitochondrial dysfunction accompanied by bioenergetic failure is a pathological hallmark of major neurodegenerative diseases. Brain injury triggers acute mitochondrial damage and a local energy crisis that accelerates neuron death. Thus, mitochondrial maintenance defects and axonal energy deficits emerge as central problems in neurodegenerative disorders and brain injury. Recent studies have started to uncover the intrinsic mechanisms that neurons adopt to maintain (or reprogram) axonal mitochondrial density and integrity, and their bioenergetic capacity, upon sensing energy stress. In this review, we discuss recent advances in how neurons maintain a healthy pool of axonal mitochondria, as well as potential therapeutic strategies that target bioenergetic restoration to power neuronal survival, function, and regeneration.

Free Radical Biology and Medicine, Mar 1, 2021

Current Biology, Jul 1, 2021

Mitochondria supply adenosine triphosphate (ATP) essential for neuronal survival and regeneration... more Mitochondria supply adenosine triphosphate (ATP) essential for neuronal survival and regeneration. Brain injury and ischemia trigger acute mitochondrial damage and a local energy crisis, leading to degeneration. Boosting local ATP supply in injured axons is thus critical to meet increased energy demand during nerve repair and regeneration in adult brains, where mitochondria remain largely stationary. Here, we elucidate an intrinsic energetic repair signaling axis that boosts axonal energy supply by reprogramming mitochondrial trafficking and anchoring in response to acute injury-ischemic stress in mature neurons and adult brains. P21-activated kinase 5 (PAK5) is a brain mitochondrial kinase with declined expression in mature neurons. PAK5 synthesis and signaling is spatiotemporally activated within axons in response to ischemic stress and axonal injury. PAK5 signaling remobilizes and replaces damaged mitochondria via the phosphorylation switch that turns off the axonal mitochondrial anchor syntaphilin. Injury-ischemic insults trigger AKT growth signaling that activates PAK5 and boosts local energy supply, thus protecting axon survival and facilitating regeneration in in vitro and in vivo models. Our study reveals an axonal mitochondrial signaling axis that responds to injury and ischemia by remobilizing damaged mitochondria for replacement, thereby maintaining local energy supply to support central nervous system (CNS) survival and regeneration.

Brain

Spinal bulbar muscular atrophy (SBMA), the first identified CAG-repeat expansion disorder, is an ... more Spinal bulbar muscular atrophy (SBMA), the first identified CAG-repeat expansion disorder, is an X-linked neuromuscular disorder involving CAG-repeat-expansion mutations in the androgen receptor (AR) gene. We utilized CRISPR-Cas9 gene editing to engineer novel isogenic human induced pluripotent stem cell (hiPSC) models, consisting of isogenic AR knockout, control and disease lines expressing mutant AR with distinct repeat lengths, as well as control and disease lines expressing FLAG-tagged wild-type and mutant AR, respectively. Adapting a small-molecule cocktail-directed approach, we differentiate the isogenic hiPSC models into motor neuron-like cells with a highly enriched population to uncover cell-type-specific mechanisms underlying SBMA and to distinguish gain- from loss-of-function properties of mutant AR in disease motor neurons. We demonstrate that ligand-free mutant AR causes drastic mitochondrial dysfunction in neurites of differentiated disease motor neurons due to gain-of...

Biochemical and Biophysical Research Communications, 2000

Rat nonmuscle myosin heavy chain-B (r-nmMHC-B) mRNA was previously found downregulated in Rat 6 f... more Rat nonmuscle myosin heavy chain-B (r-nmMHC-B) mRNA was previously found downregulated in Rat 6 fibroblasts transformed by mutant p53val135 [J. W. P. Yam, J. Y. Zheng, and W. L. W. Hsiao (1987) Biochem. Biophys. Res. Commun. 266, 472–480]. Overexpression of exogenous r-nmMHC-B could partially reverse the transforming phenotypes both in vitro and in vivo. The downregulation of r-nmMHC-B was also

European Journal of Neuroscience, 2002

Neurotransmitter release is triggered by Ca 2+-in¯ux through multiple sub-types of high voltage-a... more Neurotransmitter release is triggered by Ca 2+-in¯ux through multiple sub-types of high voltage-activated Ca 2+-channels. Tottering mice have a mutation in the a1A pore-forming subunit of P-and Q-type Ca 2+-channels, two prominent sub-types that regulate transmitter release from central nerve terminals. Immunoblotting analysis of puri®ed forebrain terminals from tottering mice revealed an 85% reduction in the protein expression level of the mutated a1A subunit compared to expression of the a1A subunit in wild-type terminals. In contrast, the expression of the a1B subunit of the N-type Ca 2+-channels was unchanged. Release of the amino acids glutamate and GABA and of the neuropeptide cholecystokinin (CCK) induced by a short (100 ms) depolarization pulse was unchanged in the terminals of tottering mice. Studies using speci®c blockers of Ca 2+-channels however, revealed a reduced contribution of P-and Q-type Ca 2+-channels to glutamate and cholecystokinin release, whereas a greater reliance on N-type Ca 2+-channels for release of these transmitters was observed. In contrast, the contribution of the P-, Q-and N-type Ca 2+-channels to the release of GABA was not altered in tottering mice. These results indicate that the expression of the a1A subunit was decreased in terminals from tottering mice, and that a decreased contribution of P-and Q-type Ca 2+-channels to the release of glutamate and cholecystokinin was functionally compensated by an increased contribution of N-type Ca 2+-channels.

Nature Reviews Neuroscience, Nov 15, 2021

Synaptic activity imposes large energy demands that are met by local adenosine triphosphate (ATP)... more Synaptic activity imposes large energy demands that are met by local adenosine triphosphate (ATP) synthesis through glycolysis and mitochondrial oxidative phosphorylation. ATP drives action potentials, supports synapse assembly and remodelling, and fuels synaptic vesicle filling and recycling, thus sustaining synaptic transmission. Given their polarized morphological features — including long axons and extensive branching in their terminal regions — neurons face exceptional challenges in maintaining presynaptic energy homeostasis, particularly during intensive synaptic activity. Recent studies have started to uncover the mechanisms and signalling pathways involved in activity-dependent and energy-sensitive regulation of presynaptic energetics, or ‘synaptoenergetics’. These conceptual advances have established the energetic regulation of synaptic efficacy and plasticity as an exciting research field that is relevant to a range of neurological disorders associated with bioenergetic failure and synaptic dysfunction. Numerous energy-demanding cellular processes contribute to synaptic activity and function. Li and Sheng describe the mechanisms that regulate presynaptic energy supply to ensure that neurons can meet these demands and maintain their functions during periods of intensive synaptic activity.

The Journal of Neuroscience, Jul 29, 2009

Mitochondria in the cell bodies of neurons are transported down neuronal processes in response to... more Mitochondria in the cell bodies of neurons are transported down neuronal processes in response to changes in local energy and metabolic states. Because of their extreme polarity, neurons require specialized mechanisms to regulate mitochondrial transport and retention in axons. Our previous studies using syntaphilin (snph) knockout mice provided evidence that SNPH targets to axonal mitochondria and controls their mobility through its static interaction with microtubules (MTs). However, the mechanisms regulating SNPH-mediated mitochondrial docking remain elusive. Here, we report an unexpected role for dynein light chain LC8. Using proteomic biochemical and cell biological assays combined with time-lapse imaging in live snph wild-type and mutant neurons, we reveal that LC8 regulates axonal mitochondrial mobility by binding to SNPH, thus enhancing the SNPH-MT docking interaction. Using mutagenesis assays, we mapped a seven-residue LC8-binding motif. Through this specific interaction, SNPH recruits LC8 to axonal mitochondria; such colocalization is abolished when neurons express SNPH mutants lacking the LC8-binding motif. Transient LC8 expression reduces mitochondrial mobility in snph (ϩ/ϩ) but not (Ϫ/Ϫ) neurons, suggesting that the observed effect of LC8 depends on the SNPH-mediated docking mechanism. In contrast, deleting the LC8-binding motif impairs the ability of SNPH to immobilize axonal mitochondria. Furthermore, circular dichroism spectrum analysis shows that LC8 stabilizes an ␣-helical coiled-coil within the MT-binding domain of SNPH against thermal unfolding. Thus, our study provides new mechanistic insights into controlling mitochondrial mobility through a dynamic interaction between the mitochondrial docking receptor and axonal cytoskeleton.

Cell Metabolism, Mar 1, 2020

Highlights d Injury-induced mitochondrial dysfunction contributes to CNS axonal regenerative fail... more Highlights d Injury-induced mitochondrial dysfunction contributes to CNS axonal regenerative failure d Enhancing its transport recovers mitochondrial integrity after spinal cord injury (SCI) d Removing a mitochondrial anchor protein enhances functional recovery after SCI d Increasing energy metabolism via creatine treatment promotes axon regeneration after SCI

Pharmacology & Therapeutics, 2005

Activity-dependent modulation of synaptic function and structure is emerging as one of the key me... more Activity-dependent modulation of synaptic function and structure is emerging as one of the key mechanisms underlying synaptic plasticity. Whereas over the past decade considerable progress has been made in identifying postsynaptic mechanisms for synaptic plasticity, the presynaptic mechanisms involved have remained largely elusive. Recent evidence implicates that second messenger regulation of the protein interactions in synaptic vesicle release machinery is one mechanism by which cellular events modulate synaptic transmission. Thus, identifying protein kinases and their targets in nerve terminals, particularly those functionally regulated by synaptic activity or intracellular [Ca 2+ ], is critical to the elucidation of the molecular mechanisms underlying modulation of neurotransmitter release and presynaptic plasticity. The phosphorylation and dephosphorylation states of synaptic proteins that mediate vesicle exocytosis could regulate the biochemical pathways leading from synaptic vesicle docking to fusion. However, functional evaluation of the activity-dependent phosphorylation events for modulating presynaptic functions still represents a considerable challenge. Here, we present a brief overview of the data on the newly identified candidate targets of the second messenger-activated protein kinases in the presynaptic release machinery and discuss the potential impact of these phosphorylation events in synaptic strength and presynaptic plasticity.

Journal of Cell Biology, Mar 31, 2014