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A Neurotoxic Phospholipase A2 Impairs Yeast Amphiphysin Activity and Reduces Endocytosis  [PDF]
Mojca Mattiazzi, Yidi Sun, Heimo Wolinski, Andrej Bavdek, Toni Petan, Gregor Anderluh, Sepp D. Kohlwein, David G. Drubin, Igor Kri?aj, Uro? Petrovi?
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040931
Abstract: Background Presynaptically neurotoxic phospholipases A2 inhibit synaptic vesicle recycling through endocytosis. Principal Findings Here we provide insight into the action of a presynaptically neurotoxic phospholipase A2 ammodytoxin A (AtxA) on clathrin-dependent endocytosis in budding yeast. AtxA caused changes in the dynamics of vesicle formation and scission from the plasma membrane in a phospholipase activity dependent manner. Our data, based on synthetic dosage lethality screen and the analysis of the dynamics of sites of endocytosis, indicate that AtxA impairs the activity of amphiphysin. Conclusions We identified amphiphysin and endocytosis as the target of AtxA intracellular activity. We propose that AtxA reduces endocytosis following a mechanism of action which includes both a specific protein–protein interaction and enzymatic activity, and which is applicable to yeast and mammalian cells. Knowing how neurotoxic phospholipases A2 work can open new ways to regulate endocytosis.
Regulation of thalamocortical axon branching by BDNF and synaptic vesicle cycling  [PDF]
Bj?rn Granseth,Leon Lagnado,Nobuhiko Yamamoto
Frontiers in Neural Circuits , 2013, DOI: 10.3389/fncir.2013.00202
Abstract: During development, axons form branches in response to extracellular molecules. Little is known about the underlying molecular mechanisms. Here, we investigate how neurotrophin-induced axon branching is related to synaptic vesicle cycling for thalamocortical axons. The exogenous application of brain-derived neurotrophic factor (BDNF) markedly increased axon branching in thalamocortical co-cultures, while removal of endogenous BDNF reduced branching. Over-expression of a C-terminal fragment of AP180 that inhibits clathrin-mediated endocytosis affected the laminar distribution and the number of branch points. A dominant-negative synaptotagmin mutant that selectively targets synaptic vesicle cycling, strongly suppressed axon branching. Moreover, axons expressing the mutant synaptotagmin were resistant to the branch-promoting effect of BDNF. These results suggest that synaptic vesicle cycling might regulate BDNF induced branching during the development of the axonal arbor.
Regulation of Synaptic Vesicle Docking by Different Classes of Macromolecules in Active Zone Material  [PDF]
Joseph A. Szule, Mark L. Harlow, Jae Hoon Jung, Francisco F. De-Miguel, Robert M. Marshall, Uel J. McMahan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033333
Abstract: The docking of synaptic vesicles at active zones on the presynaptic plasma membrane of axon terminals is essential for their fusion with the membrane and exocytosis of their neurotransmitter to mediate synaptic impulse transmission. Dense networks of macromolecules, called active zone material, (AZM) are attached to the presynaptic membrane next to docked vesicles. Electron tomography has shown that some AZM macromolecules are connected to docked vesicles, leading to the suggestion that AZM is somehow involved in the docking process. We used electron tomography on the simply arranged active zones at frog neuromuscular junctions to characterize the connections of AZM to docked synaptic vesicles and to search for the establishment of such connections during vesicle docking. We show that each docked vesicle is connected to 10–15 AZM macromolecules, which fall into four classes based on several criteria including their position relative to the presynaptic membrane. In activated axon terminals fixed during replacement of docked vesicles by previously undocked vesicles, undocked vesicles near vacated docking sites on the presynaptic membrane have connections to the same classes of AZM macromolecules that are connected to docked vesicles in resting terminals. The number of classes and the total number of macromolecules to which the undocked vesicles are connected are inversely proportional to the vesicles’ distance from the presynaptic membrane. We conclude that vesicle movement toward and maintenance at docking sites on the presynaptic membrane are directed by an orderly succession of stable interactions between the vesicles and distinct classes of AZM macromolecules positioned at different distances from the membrane. Establishing the number, arrangement and sequence of association of AZM macromolecules involved in vesicle docking provides an anatomical basis for testing and extending concepts of docking mechanisms provided by biochemistry.
Differential Regulation of Synaptic Vesicle Tethering and Docking by UNC-18 and TOM-1  [PDF]
Elena O. Gracheva,Ed B. Maryon,Martine Berthelot-Grosjean,Janet E. Richmond
Frontiers in Synaptic Neuroscience , 2010, DOI: 10.3389/fnsyn.2010.00141
Abstract: The assembly of SNARE complexes between syntaxin, SNAP-25 and synaptobrevin is required to prime synaptic vesicles for fusion. Since Munc18 and tomosyn compete for syntaxin interactions, the interplay between these proteins is predicted to be important in regulating synaptic transmission. We explored this possibility, by examining genetic interactions between C. elegans unc-18(Munc18), unc-64(syntaxin) and tom-1(tomosyn). We have previously demonstrated that unc-18 mutants have reduced synaptic transmission, whereas tom-1 mutants exhibit enhanced release. Here we show that the unc-18 mutant release defect is associated with loss of two morphologically distinct vesicle pools; those tethered within 25 nm of the plasma membrane and those docked with the plasma membrane. In contrast, priming defective unc-13 mutants accumulate tethered vesicles, while docked vesicles are greatly reduced, indicating tethering is UNC-18-dependent and occurs in the absence of priming. C. elegans unc-64 mutants phenocopy unc-18 mutants, losing both tethered and docked vesicles, whereas overexpression of open syntaxin preferentially increases vesicle docking, suggesting UNC-18/closed syntaxin interactions are responsible for vesicle tethering. Given the competition between vertebrate tomosyn and Munc18, for syntaxin binding, we hypothesized that C. elegans TOM-1 may inhibit both UNC-18-dependent vesicle targeting steps. Consistent with this hypothesis, tom-1 mutants exhibit enhanced UNC-18 plasma membrane localization and a concomitant increase in both tethered and docked synaptic vesicles. Furthermore, in tom-1;unc-18 double mutants the docked, primed vesicle pool is preferentially rescued relative to unc-18 single mutants. Together these data provide evidence for the differential regulation of two vesicle targeting steps by UNC-18 and TOM-1 through competitive interactions with syntaxin.
The regulation of endocytosis by kinases: cell biology meets genomics
Zita Balklava, Barth D Grant
Genome Biology , 2006, DOI: 10.1186/gb-2005-6-13-245
Abstract: Since the discovery in the nematode Caenorhabditis elegans that the introduction of a double-stranded RNA (dsRNA) trigger can lead to the selective inhibition of gene expression in a sequence-specific manner [1], this phenomenon - now widely known as RNA interference (RNAi) - has spawned many new applications. Among these is the invention of a whole area of genomics research dedicated to studying RNAi-induced phenotypes. Such phenotypes generally mimic reduction-of-function or loss-of-function mutations that have formed the backbone of traditional genetics research for more than a century. Most large-scale screens using this method have been performed in model organisms such as C. elegans [2-4] and Drosophila melanogaster [5,6]. As a result of recent insights into the mechanism of RNAi and the resulting identification of small interfering RNAs (siRNAs), such large-scale approaches are now also feasible in cultured mammalian cells [7,8]. The quantity of data derived from large-scale or whole-genome RNAi-based screens, while sometimes overwhelming, has begun to provide insights into complex biological phenomena that had previously proved intractable [4,9]. Endocytosis is one such complex cellular process that has begun to give up its secrets to the RNAi cognoscenti. In this article we focus on a recent report by Marino Zerial and colleagues [10] who utilize cutting-edge techniques to perform a genome-wide RNAi screen exploring the role of each human kinase in the regulation of endocytosis.Endocytosis uses membrane-bound vesicles to internalize macromolecules and fluid from the plasma membrane and extracellular space and is a crucial process for all eukaryotic cells. Endocytosis mediates a plethora of biological processes including nutrient uptake, regulation of growth factor receptors, synaptic vesicle recycling by the nervous system, and antigen processing by the immune system. Recent RNAi-based studies provide new insights into the regulation of the best studied pat
Syntaxin 1B, but Not Syntaxin 1A, Is Necessary for the Regulation of Synaptic Vesicle Exocytosis and of the Readily Releasable Pool at Central Synapses  [PDF]
Tatsuya Mishima, Tomonori Fujiwara, Masumi Sanada, Takefumi Kofuji, Masami Kanai-Azuma, Kimio Akagawa
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0090004
Abstract: Two syntaxin 1 (STX1) isoforms, HPC-1/STX1A and STX1B, are coexpressed in neurons and function as neuronal target membrane (t)-SNAREs. However, little is known about their functional differences in synaptic transmission. STX1A null mutant mice develop normally and do not show abnormalities in fast synaptic transmission, but monoaminergic transmissions are impaired. In the present study, we found that STX1B null mutant mice died within 2 weeks of birth. To examine functional differences between STX1A and 1B, we analyzed the presynaptic properties of glutamatergic and GABAergic synapses in STX1B null mutant and STX1A/1B double null mutant mice. We found that the frequency of spontaneous quantal release was lower and the paired-pulse ratio of evoked postsynaptic currents was significantly greater in glutamatergic and GABAergic synapses of STX1B null neurons. Deletion of STX1B also accelerated synaptic vesicle turnover in glutamatergic synapses and decreased the size of the readily releasable pool in glutamatergic and GABAergic synapses. Moreover, STX1A/1B double null neurons showed reduced and asynchronous evoked synaptic vesicle release in glutamatergic and GABAergic synapses. Our results suggest that although STX1A and 1B share a basic function as neuronal t-SNAREs, STX1B but not STX1A is necessary for the regulation of spontaneous and evoked synaptic vesicle exocytosis in fast transmission.
Synaptic Vesicle Pools: An Update  [PDF]
Annette Denker,Silvio O. Rizzoli
Frontiers in Synaptic Neuroscience , 2010, DOI: 10.3389/fnsyn.2010.00135
Abstract: During the last few decades synaptic vesicles have been assigned to a variety of functional and morphological classes or “pools”. We have argued in the past (Rizzoli and Betz, 2005) that synaptic activity in several preparations is accounted for by the function of three vesicle pools: the readily releasable pool (docked at active zones and ready to go upon stimulation), the recycling pool (scattered throughout the nerve terminals and recycling upon moderate stimulation), and finally the reserve pool (occupying most of the vesicle clusters and only recycling upon strong stimulation). We discuss here the advancements in the vesicle pool field which took place in the ensuing years, focusing on the behavior of different pools under both strong stimulation and physiological activity. Several new findings have enhanced the three-pool model, with, for example, the disparity between recycling and reserve vesicles being underlined by the observation that the former are mobile, while the latter are “fixed”. Finally, a number of altogether new concepts have also evolved such as the current controversy on the identity of the spontaneously recycling vesicle pool.
Differential Roles for Snapin and Synaptotagmin in the Synaptic Vesicle Cycle  [PDF]
Szi-Chieh Yu, Susan M. Klosterman, Ashley A. Martin, Elena O. Gracheva, Janet E. Richmond
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057842
Abstract: Evoked synaptic transmission is dependent on interactions between the calcium sensor Synaptotagmin I and the SNARE complex, comprised of Syntaxin, SNAP-25, and Synaptobrevin. Recent evidence suggests that Snapin may be an important intermediate in this process, through simultaneous interactions of Snapin dimers with SNAP-25 and Synaptotagmin. In support of this model, cultured neurons derived from embryonically lethal Snapin null mutant mice exhibit desynchronized release and a reduced readily releasable vesicle pool. Based on evidence that a dimerization-defective Snapin mutation specifically disrupts priming, Snapin is hypothesized to stabilize primed vesicles by structurally coupling Synaptotagmin and SNAP-25. To explore this model in vivo we examined synaptic transmission in viable, adult C. elegans Snapin (snpn-1) mutants. The kinetics of synaptic transmission were unaffected at snpn-1 mutant neuromuscular junctions (NMJs), but the number of docked, fusion competent vesicles was significantly reduced. However, analyses of snt-1 and snt-1;snpn-1 double mutants suggest that the docking role of SNPN-1 is independent of Synaptotagmin. Based on these results we propose that the primary role of Snapin in C. elegans is to promote vesicle priming, consistent with the stabilization of SNARE complex formation through established interactions with SNAP-25 upstream of the actions of Synaptotagmin in calcium-sensing and endocytosis.
Nonmuscle Myosin II helps regulate synaptic vesicle mobility at the Drosophila neuromuscular junction
Sara Seabrooke, Xinping Qiu, Bryan A Stewart
BMC Neuroscience , 2010, DOI: 10.1186/1471-2202-11-37
Abstract: In the present study we have identified Nonmuscle Myosin II as a candidate molecule important for synaptic vesicle traffic within Drosophila larval neuromuscular boutons. Nonmuscle Myosin II was found to be localized at the Drosophila larval neuromuscular junction; genetics and pharmacology combined with the time-lapse imaging technique FRAP were used to reveal a contribution of Nonmuscle Myosin II to synaptic vesicle movement. FRAP analysis showed that vesicle dynamics were highly dependent on the expression level of Nonmuscle Myosin II.Our results provide evidence that Nonmuscle Myosin II is present presynaptically, is important for synaptic vesicle mobility and suggests a role for Nonmuscle Myosin II in shuttling vesicles at the Drosophila neuromuscular junction. This work begins to reveal the process by which synaptic vesicles traverse within the bouton.Transport and assembly of synaptic vesicles has been the subject of several studies. Vesicles and their components are transported along axon microtubules to the nerve terminal, (for review see [1,2]) where they participate in synaptic physiology, undergoing a cycle of exo- and endocytosis. However, vesicle traffic within terminal boutons is not well understood although recent advances in this area have been made [3,4].Classically, vesicles were believed to be relatively stationary until released [5-7]. However, more recent studies provided evidence for a mobile vesicle pool [8,9] best described by a caged-diffusion model [10] and differential vesicle mobility in the reserve and recycling pool has been suggested within the frog motor nerve terminals [11]. Additionally, Nunes et al. [12] observed dynamic vesicles in the Drosophila melanogaster bouton, and dynamic vesicles have been reported at ribbon synapses in lizards [13].Vesicle movement may result from diffusion or directed transport. Actin polymerization in the nerve terminal may promote vesicle movement through a Listeria comet mechanism [14] or it may act
Drosophila cyfip Regulates Synaptic Development and Endocytosis by Suppressing Filamentous Actin Assembly  [PDF]
Lu Zhao equal contributor,Dan Wang equal contributor,Qifu Wang,Avital A. Rodal,Yong Q. Zhang
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003450
Abstract: The formation of synapses and the proper construction of neural circuits depend on signaling pathways that regulate cytoskeletal structure and dynamics. After the mutual recognition of a growing axon and its target, multiple signaling pathways are activated that regulate cytoskeletal dynamics to determine the morphology and strength of the connection. By analyzing Drosophila mutations in the cytoplasmic FMRP interacting protein Cyfip, we demonstrate that this component of the WAVE complex inhibits the assembly of filamentous actin (F-actin) and thereby regulates key aspects of synaptogenesis. Cyfip regulates the distribution of F-actin filaments in presynaptic neuromuscular junction (NMJ) terminals. At cyfip mutant NMJs, F-actin assembly was accelerated, resulting in shorter NMJs, more numerous satellite boutons, and reduced quantal content. Increased synaptic vesicle size and failure to maintain excitatory junctional potential amplitudes under high-frequency stimulation in cyfip mutants indicated an endocytic defect. cyfip mutants exhibited upregulated bone morphogenetic protein (BMP) signaling, a major growth-promoting pathway known to be attenuated by endocytosis at the Drosophila NMJ. We propose that Cyfip regulates synapse development and endocytosis by inhibiting actin assembly.
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