Publications by authors named "Junhua Geng"

5 Publications

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Neurexin and Neuroligins Maintain the Balance of Ghost and Satellite Boutons at the Neuromuscular Junction.

Front Neuroanat 2020 9;14:19. Epub 2020 Jun 9.

The Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing, China.

Neurexins and neuroligins are common synaptic adhesion molecules that are associated with autism and interact with each other in the synaptic cleft. The neuromuscular junction (NMJ) bouton is a well-known model system in neuroscience, and ghost and satellite boutons, respectively, indicate the poor development and overgrowth of the NMJ boutons. However, the neurexin (DNrx) and neuroligins (DNlgs) are mainly observed in type Ib boutons, indicating the ultrastructural and developmental phenotypes of the NMJ. Here, we identified the ultrastructural and developmental features of ghost and satellite boutons by utilizing () and () fly mutants and other associated fly strains. Ghost boutons contain synaptic vesicles with multiple diameters but very rarely contain T-bar structures and swollen or thin subsynaptic reticulum (SSR) membranes. The muscle cell membrane is invaginated at different sites, stretches to the ghost bouton from different directions, forms several layers that enwrap the ghost bouton, and then branches into the complex SSR. Satellite boutons share a common SSR membrane and present either a typical profile in which a main bouton is encircled by small boutons or two atypical profiles in which the small boutons are grouped together or distributed in beads without a main bouton. Electron and confocal microscopy data showed that , , , , and mutations led to ghost boutons; the overexpression of , , , , and led to satellite boutons; and the double mutation also led to satellite boutons. These results suggested that DNrx and DNlgs jointly maintain the development and function of NMJ boutons by regulating the balance of ghost and satellite boutons in .
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http://dx.doi.org/10.3389/fnana.2020.00019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296126PMC
June 2020

Activity-Induced Synaptic Structural Modifications by an Activator of Integrin Signaling at the Neuromuscular Junction.

J Neurosci 2017 03 20;37(12):3246-3263. Epub 2017 Feb 20.

Zilkha Neurogenetic Institute and

Activity-induced synaptic structural modification is crucial for neural development and synaptic plasticity, but the molecular players involved in this process are not well defined. Here, we report that a protein named Shriveled (Shv) regulates synaptic growth and activity-dependent synaptic remodeling at the neuromuscular junction. Depletion of Shv causes synaptic overgrowth and an accumulation of immature boutons. We find that Shv physically and genetically interacts with βPS integrin. Furthermore, Shv is secreted during intense, but not mild, neuronal activity to acutely activate integrin signaling, induce synaptic bouton enlargement, and increase postsynaptic glutamate receptor abundance. Consequently, loss of Shv prevents activity-induced synapse maturation and abolishes post-tetanic potentiation, a form of synaptic plasticity. Our data identify Shv as a novel trans-synaptic signal secreted upon intense neuronal activity to promote synapse remodeling through integrin receptor signaling. The ability of neurons to rapidly modify synaptic structure in response to neuronal activity, a process called activity-induced structural remodeling, is crucial for neuronal development and complex brain functions. The molecular players that are important for this fundamental biological process are not well understood. Here we show that the Shriveled (Shv) protein is required during development to maintain normal synaptic growth. We further demonstrate that Shv is selectively released during intense neuronal activity, but not mild neuronal activity, to acutely activate integrin signaling and trigger structural modifications at the neuromuscular junction. This work identifies Shv as a key modulator of activity-induced structural remodeling and suggests that neurons use distinct molecular cues to differentially modulate synaptic growth and remodeling to meet synaptic demand.
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http://dx.doi.org/10.1523/JNEUROSCI.3128-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373117PMC
March 2017

Phosphorylation of Synaptojanin Differentially Regulates Endocytosis of Functionally Distinct Synaptic Vesicle Pools.

J Neurosci 2016 08;36(34):8882-94

Zilkha Neurogenetic Institute, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, and Neuroscience Graduate Program, University of Southern California, Los Angeles, California 90089

Unlabelled: The rapid replenishment of synaptic vesicles through endocytosis is crucial for sustaining synaptic transmission during intense neuronal activity. Synaptojanin (Synj), a phosphoinositide phosphatase, is known to play an important role in vesicle recycling by promoting the uncoating of clathrin following synaptic vesicle uptake. Synj has been shown to be a substrate of the minibrain (Mnb) kinase, a fly homolog of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); however, the functional impacts of Synj phosphorylation by Mnb are not well understood. Here we identify that Mnb phosphorylates Synj at S1029 in Drosophila We find that phosphorylation of Synj at S1029 enhances Synj phosphatase activity, alters interaction between Synj and endophilin, and promotes efficient endocytosis of the active cycling vesicle pool (also referred to as exo-endo cycling pool) at the expense of reserve pool vesicle endocytosis. Dephosphorylated Synj, on the other hand, is deficient in the endocytosis of the active recycling pool vesicles but maintains reserve pool vesicle endocytosis to restore total vesicle pool size and sustain synaptic transmission. Together, our findings reveal a novel role for Synj in modulating reserve pool vesicle endocytosis and further indicate that dynamic phosphorylation and dephosphorylation of Synj differentially maintain endocytosis of distinct functional synaptic vesicle pools.

Significance Statement: Synaptic vesicle endocytosis sustains communication between neurons during a wide range of neuronal activities by recycling used vesicle membrane and protein components. Here we identify that Synaptojanin, a protein with a known role in synaptic vesicle endocytosis, is phosphorylated at S1029 in vivo by the Minibrain kinase. We further demonstrate that the phosphorylation status of Synaptojanin at S1029 differentially regulates its participation in the recycling of distinct synaptic vesicle pools. Our results reveal a new role for Synaptojanin in maintaining synaptic vesicle pool size and in reserve vesicle endocytosis. As Synaptojanin and Minibrain perturbations are associated with various neurological disorders, such as Parkinson's, autism, and Down syndrome, understanding mechanisms modulating Synaptojanin function provides valuable insights into processes affecting neuronal communication.
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http://dx.doi.org/10.1523/JNEUROSCI.1470-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995302PMC
August 2016

Cycloheximide Treatment Causes a ZVAD-Sensitive Protease-Dependent Cleavage of Human Tau in Drosophila Cells.

J Alzheimers Dis 2016 ;49(4):1161-8

State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, College of Life Sciences, Beijing Normal University, Beijing, China.

Neurofibrillary tangles are the main pathological feature of Alzheimer's disease. Insoluble tau protein is the major component of neurofibrillary tangles. Defects in the tau protein degradation pathway in neurons can lead to the accumulation of tau and its subsequent aggregation. Currently, contradictory results on the tau degradation pathway have been reported by different groups. This discrepancy is most likely due to different cell lines and methods used in those studies. In this study, we found that cycloheximide treatment induced mild activation of a ZVAD-sensitive protease in Drosophila Kc cells, resulting in cleavage of tau at its C-terminus; this cleavage could generate misleading tau protein degradation pattern results depending on the antibodies used in the assay. Because cycloheximide is a broadly used chemical reagent for the study of protein degradation, the unexpected artificial effect we observed here indicates that cycloheximide is not suitable for the study of tau degradation. Other methods, such as inducible expression systems and pulse-chase assays, may be more appropriate for studying tau degradation under physiological conditions.
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http://dx.doi.org/10.3233/JAD-150423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927919PMC
October 2016

The C-terminus of tau protein plays an important role in its stability and toxicity.

J Mol Neurosci 2015 Jan 2;55(1):251-259. Epub 2014 May 2.

State Key Laboratory of Cognitive Neuroscience and Learning and IDG/McGovern Institute for Brain Research, College of Life Sciences, Beijing Normal University, Beijing, China.

The identification of tau fragments generated by proteolysis in the neurons of AD patients and in neurofibrillary tangles encourages research on the toxicity of truncated tau. However, the detailed mechanism underlying the proteolysis-induced toxicity of tau is not clear and even controversial in some cases. In the present study, we used Drosophila as a model to evaluate the toxicity of a set of truncated tau fragments in vivo and found that the flies harboring C-terminal-truncated tau exhibited less toxicity due to the unstable characteristic of C-terminal-truncated tau fragments. Further study carried out in cultured Drosophila Kc cells revealed that C-terminal-truncated tau fragments degrade faster than full-length tau or N-terminal-truncated fragments. Collectively, our data implicate proteolysis of tau as an important pathway mediating tau degradation and neurotoxicity in vivo.
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http://dx.doi.org/10.1007/s12031-014-0314-7DOI Listing
January 2015
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