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https://www.readbyqxmd.com/read/28331029/the-sac1-domain-in-synaptojanin-is-required-for%C3%A2-autophagosome-maturation-at-presynaptic%C3%A2-terminals
#1
Roeland Vanhauwaert, Sabine Kuenen, Roy Masius, Adekunle Bademosi, Julia Manetsberger, Nils Schoovaerts, Laura Bounti, Serguei Gontcharenko, Jef Swerts, Sven Vilain, Marina Picillo, Paolo Barone, Shashini T Munshi, Femke Ms de Vrij, Steven A Kushner, Natalia V Gounko, Wim Mandemakers, Vincenzo Bonifati, Frederic A Meunier, Sandra-Fausia Soukup, Patrik Verstreken
Presynaptic terminals are metabolically active and accrue damage through continuous vesicle cycling. How synapses locally regulate protein homeostasis is poorly understood. We show that the presynaptic lipid phosphatase synaptojanin is required for macroautophagy, and this role is inhibited by the Parkinson's disease mutation R258Q. Synaptojanin drives synaptic endocytosis by dephosphorylating PI(4,5)P2, but this function appears normal in Synaptojanin(RQ) knock-in flies. Instead, R258Q affects the synaptojanin SAC1 domain that dephosphorylates PI(3)P and PI(3,5)P2, two lipids found in autophagosomal membranes...
March 22, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28325932/a-stochastic-model-of-active-zone-material-mediated-synaptic-vesicle-docking-and-priming-at-resting-active-zones
#2
Jae Hoon Jung, Sebatian Doniach
Synaptic vesicles (SVs) fuse with the presynaptic membrane (PM) at specialized regions called active zones for synaptic transmission. SVs are associated with dense aggregates of macromolecules called active zone material (AZM) that has been thought to be involved in SV release. However, its role has recently begun to be elucidated. Several morphological studies proposed distinctively different AZM mediated SV docking and priming models: sequential and concurrent SV docking/priming. To explore ways to reconcile the contradictory models we develop a stochastic AZM mediated SV docking and priming model...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28317021/the-bloc-1-subunit-pallidin-facilitates-activity-dependent-synaptic-vesicle-recycling
#3
Xun Chen, Wenpei Ma, Shixing Zhang, Jeremy Paluch, Wanlin Guo, Dion K Dickman
Membrane trafficking pathways must be exquisitely coordinated at synaptic terminals to maintain functionality, particularly during conditions of high activity. We have generated null mutations in the Drosophila homolog of pallidin, a central subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), to determine its role in synaptic development and physiology. We find that Pallidin localizes to presynaptic microtubules and cytoskeletal structures, and that the stability of Pallidin protein is highly dependent on the BLOC-1 components Dysbindin and Blos1...
January 2017: ENeuro
https://www.readbyqxmd.com/read/28314816/characterization-of-a-human-point-mutation-of-vglut3-p-a211v-in-the-rodent-brain-suggests-a-non-uniform-distribution-of-the-transporter-in-synaptic-vesicles
#4
Lauriane Ramet, Johannes Zimmermann, Tiphaine Bersot, Odile Poirel, Stéphanie De Gois, Katlin Silm, Diana Yae Sakae, Nina Mansouri-Guilani, Marie-Josée Bourque, Louis-Eric Trudeau, Nicolas Pietrancosta, Stéphanie Daumas, Véronique Bernard, Christian Rosenmund, Salah El Mestikawy
The atypical vesicular glutamate transporter type 3 (VGLUT3) is expressed by sub-populations of neurons using acetylcholine, GABA or serotonin as neurotransmitters. In addition, VGLUT3 is expressed in the inner hair cells of the auditory system. A mutation (p.A211V) in the gene that encodes VGLUT3 is responsible for progressive deafness in two unrelated families. In this study, we investigated the consequences of the p.A211V mutation in cell cultures and in the central nervous system (CNS) of a mutant mouse...
March 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28314159/aging-alters-the-molecular-dynamics-of-synapses-in-a-sexually-dimorphic-pattern-in-zebrafish-danio-rerio
#5
Elif Tugce Karoglu, Dilara Ozge Halim, Bahriye Erkaya, Ferda Altaytas, Ayca Arslan-Ergul, Ozlen Konu, Michelle M Adams
The zebrafish has become a popular model for studying normal brain aging due to its large fecundity, conserved genome, and available genetic tools; but little data exists about neurobiological age-related alterations. The current study tested the hypothesis of an association between brain aging and synaptic protein loss across males and females. Western blot analysis of synaptophysin (SYP), a presynaptic vesicle protein, and postsynaptic density-95 (PSD-95) and gephyrin (GEP), excitatory and inhibitory postsynaptic receptor-clustering proteins, respectively, was performed in young, middle-aged, and old male and female zebrafish (Danio rerio) brains...
February 20, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28297674/nanoscale-structural-plasticity-of-the-active-zone-matrix-modulates-presynaptic-function
#6
Oleg O Glebov, Rachel E Jackson, Christian M Winterflood, Dylan M Owen, Ellen A Barker, Patrick Doherty, Helge Ewers, Juan Burrone
The active zone (AZ) matrix of presynaptic terminals coordinates the recruitment of voltage-gated calcium channels (VGCCs) and synaptic vesicles to orchestrate neurotransmitter release. However, the spatial organization of the AZ and how it controls vesicle fusion remain poorly understood. Here, we employ super-resolution microscopy and ratiometric imaging to visualize the AZ structure on the nanoscale, revealing segregation between the AZ matrix, VGCCs, and putative release sites. Long-term blockade of neuronal activity leads to reversible AZ matrix unclustering and presynaptic actin depolymerization, allowing for enrichment of AZ machinery...
March 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28295320/brefeldin-a-sensitive-mechanisms-contribute-to-endocytotic-membrane-retrieval-and-vesicle-recycling-in-cerebellar-granule-cells
#7
Alberto Rampérez, José Sánchez-Prieto, Magdalena Torres
The recycling of synaptic vesicle (SV) proteins and transmitter release both occur at multiple sites along the axon. These processes are sensitive to inhibition of the small GTP binding protein ARF1, which regulates the AP-1/AP-3 complex. As the axon matures, SV recycling becomes restricted to the presynaptic bouton, and its machinery undergoes a complex process of maturation. We used the styryl dye FM1-43 to highlight differences in the efficiency of membrane recycling at different sites in cerebellar granule cells cultured for 7 days in vitro...
March 11, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28295026/neuronal-entry-and-high-neurotoxicity-of-botulinum-neurotoxin-a-require-its-n-terminal-binding-sub-domain
#8
Jiafu Wang, Jianghui Meng, Marc Nugent, Minhong Tang, J Oliver Dolly
Botulinum neurotoxins (BoNTs) are the most toxic proteins known, due to inhibiting the neuronal release of acetylcholine and causing flaccid paralysis. Most BoNT serotypes target neurons by binding to synaptic vesicle proteins and gangliosides via a C-terminal binding sub-domain (HCC). However, the role of their conserved N-terminal sub-domain (HCN) has not been established. Herein, we created a mutant form of recombinant BoNT/A lacking HCN (rAΔHCN) and showed that the lethality of this mutant is reduced 3...
March 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28293101/new-developments-in-the-management-of-partial-onset-epilepsy-role-of-brivaracetam
#9
REVIEW
Giangennaro Coppola, Giulia Iapadre, Francesca Felicia Operto, Alberto Verrotti
Currently, a number of novel anticonvulsant drugs, the so-called third generation, are in various stages of development. Several of them are already available or in ongoing clinical trials. These new compounds should take advantage of new insights into the basic pathophysiology of epileptogenesis, drug metabolism and drug interactions. Many of them still need to be further evaluated mainly in real-world observational trials and registries. Among newer anticonvulsant drugs for partial-onset seizures (POSs), rufinamide, lacosamide, eslicarbazepine and perampanel are those new treatment options for which more substantial clinical evidence is currently available, both in adults and, to some extent, in children...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28289090/correction-elks1-localizes-the-synaptic-vesicle-priming-protein-bmunc13-2-to-a-specific-subset-of-active-zones
#10
Hiroshi Kawabe, Miso Mitkovski, Pascal S Kaeser, Johannes Hirrlinger, Felipe Opazo, Dennis Nestvogel, Stefan Kalla, Anna Fejtova, Sophie E Verrier, Simon R Bungers, Benjamin H Cooper, Frederique Varoqueaux, Yun Wang, Ralf B Nehring, Eckart D Gundelfinger, Christian Rosenmund, Silvio O Rizzoli, Thomas C Südhof, Jeong-Seop Rhee, Nils Brose
No abstract text is available yet for this article.
March 13, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28288671/microglia-derived-il-1%C3%AE-contributes-to-axon-development-disorders-and-synaptic-deficit-through-p38-mapk-signal-pathway-in-septic-neonatal-rats
#11
Qianpeng Han, Qiongyu Lin, Peixian Huang, Mengmeng Chen, Xin Hu, Hui Fu, Shaoru He, Fengcai Shen, Hongke Zeng, Yiyu Deng
BACKGROUND: Axon development plays a pivotal role in the formation of synapse, nodes of Ranvier, and myelin sheath. Interleukin-1β (IL-1β) produced by microglia may cause myelination disturbances through suppression of oligodendrocyte progenitor cell maturation in the septic neonatal rats. Here, we explored if a microglia-derived IL-1β would disturb axon development in the corpus callosum (CC) following lipopolysaccharide (LPS) administration, and if so, whether it is associated with disorder of synapse formation in the cerebral cortex and node of Ranvier...
March 14, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28286469/the-ih-channel-gene-promotes-synaptic-transmission-and-coordinated-movement-in-drosophila-melanogaster
#12
Andrew P Hegle, C Andrew Frank, Anthony Berndt, Markus Klose, Douglas W Allan, Eric A Accili
Hyperpolarization-activated cyclic nucleotide-gated "HCN" channels, which underlie the hyperpolarization-activated current (Ih), have been proposed to play diverse roles in neurons. The presynaptic HCN channel is thought to both promote and inhibit neurotransmitter release from synapses, depending upon its interactions with other presynaptic ion channels. In larvae of Drosophila melanogaster, inhibition of the presynaptic HCN channel by the drug ZD7288 reduces the enhancement of neurotransmitter release at motor terminals by serotonin but this drug has no effect on basal neurotransmitter release, implying that the channel does not contribute to firing under basal conditions...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28284392/diseases-of-the-synaptic-vesicle-a-potential-new-group-of-neurometabolic-disorders-affecting-neurotransmission
#13
E Cortès-Saladelafont, A Tristán-Noguero, R Artuch, X Altafaj, A Bayès, A García-Cazorla
The general concept of inborn error of metabolism is currently evolving into the interface between classical biochemistry and cellular biology. Basic neuroscience is providing increasing knowledge about the mechanisms of neurotransmission and novel related disorders are being described. There is a necessity of updating the classic concept of "inborn error of neurotransmitters (NT)" that considers mainly defects of synthesis and catabolism and transport of low weight NT molecules. Monogenic defects of the synaptic vesicle (SV), and especially those affecting the SV cycle are a potential new group of NT disorders since they end up in abnormal NT turnover and release...
November 2016: Seminars in Pediatric Neurology
https://www.readbyqxmd.com/read/28283886/protein-characterization-of-extracellular-microvesicles-exosomes-released-from-cytotoxin-challenged-rat-cerebrocortical-mixed-culture-and-mouse-n2a-cells
#14
Dhwani Kumar, Rachna Manek, Vijaya Raghavan, Kevin K Wang
A number of neuronal and glial proteins were previously found to be released in free-standing soluble form from cultured brain cells into cell-conditioned media. Here, we sought to examine if similar proteins are also contained in neural and astroglial cell-released extracellular microvesicles/exosomes (MV/E). In this study, MV/E were isolated from cell-conditioned media from control and cytotoxin-challenged rat cerebrocortical mixed culture (CTX) and mouse neuroblastoma N2a cells. Cytotoxin challenges included pro-necrosis calcium ionophore A23187, pro-apoptosis staurosporine (STS), and excitotoxin N-methyl-D-aspartate...
March 10, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28283675/amyotrophic-lateral-sclerosis-gene-deregulation-in-the-anterior-horn-of-the-spinal-cord-and-frontal-cortex-area-8-implications-in-frontotemporal-lobar-degeneration
#15
Pol Andrés-Benito, Jesús Moreno, Ester Aso, Mónica Povedano, Isidro Ferrer
Transcriptome arrays identifies 747 genes differentially expressed in the anterior horn of the spinal cord and 2,300 genes differentially expressed in frontal cortex area 8 in a single group of typical sALS cases without frontotemporal dementia compared with age-matched controls. Main up-regulated clusters in the anterior horn are related to inflammation and apoptosis; down-regulated clusters are linked to axoneme structures and protein synthesis. In contrast, up-regulated gene clusters in frontal cortex area 8 involve neurotransmission, synaptic proteins and vesicle trafficking, whereas main down-regulated genes cluster into oligodendrocyte function and myelin-related proteins...
March 9, 2017: Aging
https://www.readbyqxmd.com/read/28282873/crystal-structure-of-the-receptor-binding-domain-of-botulinum-neurotoxin-type-ha-also-known-as-type-fa-or-h
#16
Guorui Yao, Kwok-Ho Lam, Kay Perry, Jasmin Weisemann, Andreas Rummel, Rongsheng Jin
Botulinum neurotoxins (BoNTs), which have been exploited as cosmetics and muscle-disorder treatment medicines for decades, are well known for their extreme neurotoxicity to humans. They pose a potential bioterrorism threat because they cause botulism, a flaccid muscular paralysis-associated disease that requires immediate antitoxin treatment and intensive care over a long period of time. In addition to the existing seven established BoNT serotypes (BoNT/A-G), a new mosaic toxin type termed BoNT/HA (aka type FA or H) was reported recently...
March 8, 2017: Toxins
https://www.readbyqxmd.com/read/28280464/endogenous-leucine-rich-repeat-kinase-2-slows-synaptic-vesicle-recycling-in-striatal-neurons
#17
James W Jr Maas, Jing Yang, Robert H Edwards
Dominant mutations in leucine-rich repeat kinase 2 (LRRK2) produce the most common inherited form of Parkinson's disease (PD) but the function of LRRK2 remains poorly understood. The presynaptic role of multiple genes linked to PD including α-synuclein (α-syn) has suggested that LRRK2 may also influence neurotransmitter release, a possibility supported by recent work. However, the use of disease-associated mutants that cause toxicity complicates the analysis. To determine whether LRRK2 normally influences the synaptic vesicle, we have now used a combination of imaging and electrophysiology to study LRRK2 knockout (KO) mice...
2017: Frontiers in Synaptic Neuroscience
https://www.readbyqxmd.com/read/28280457/the-structure-of-the-synaptic-vesicle-plasma-membrane-interface-constrains-snare-models-of-rapid-synchronous-exocytosis-at-nerve-terminals
#18
REVIEW
Cameron B Gundersen
Contemporary models of neurotransmitter release invoke direct or indirect interactions between the Ca(2+) sensor, synaptotagmin and the incompletely zippered soluble, N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) complex. However, recent electron microscopic (EM) investigations have raised pragmatic issues concerning the mechanism by which SNAREs trigger membrane fusion at nerve terminals. The first issue is related to the finding that the area of contact between a "fully primed" synaptic vesicle and the plasma membrane can exceed 600 nm(2)...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28279891/efficacy-and-tolerability-of-adjunctive-brivaracetam-in-patients-with-prior-antiepileptic-drug-exposure-a-post-hoc-study
#19
Ali A Asadi-Pooya, Michael R Sperling, Steve Chung, Pavel Klein, Anyzeila Diaz, Sami Elmoufti, Jimmy Schiemann, John Whitesides
Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) for adjunctive treatment of focal (partial-onset) seizures in adults with epilepsy. This post-hoc analysis was conducted to explore the efficacy of adjunctive BRV in patients with prior levetiracetam (LEV) exposure and whether changes in efficacy were related to the similar mechanism of action of these two drugs. Data were pooled from three Phase III studies (NCT00490035; NCT00464269; NCT01261325) of adults with focal seizures taking 1-2 AEDs who received placebo or BRV 50-200mg/day without titration over a 12-week treatment period...
February 27, 2017: Epilepsy Research
https://www.readbyqxmd.com/read/28279363/synaptic-vesicle-clusters-at-synapses-a-distinct-liquid-phase
#20
REVIEW
Dragomir Milovanovic, Pietro De Camilli
Phase separation in the cytoplasm is emerging as a major principle in intracellular organization. In this process, sets of macromolecules assemble themselves into liquid compartments that are distinct from the surrounding medium but are not delimited by membrane boundaries. Here, we discuss how phase separation, in which a component of one of the two phases is vesicles rather than macromolecules, could underlie the formation of synaptic vesicle (SV) clusters in proximity to presynaptic sites. The organization of SVs into a liquid phase could explain how SVs remain tightly clustered without being stably bound to a scaffold so that they can be efficiently recruited to release site by active zone components...
March 8, 2017: Neuron
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