scholarly journals Critical role for Piccolo in Synaptic Vesicle Retrieval

2018 ◽  
Author(s):  
Frauke Ackermann ◽  
Kay O. Schink ◽  
Christine Bruns ◽  
Zsuzsanna Izsvák ◽  
F. Kent Hamra ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Active Zone ◽  
Synaptic Vesicles ◽  
Depressive Disorders ◽  
Critical Role ◽  
Neuronal Loss ◽  
Synaptic Function ◽  
Loss Of Function ◽  
Early Endosomes ◽  
Presynaptic Active Zone

AbstractLoss of function of the presynaptic active zone protein Piccolo has recently been linked to a devastating disease causing brain atrophy. Here, we address how Piccolo inactivation adversely affects synaptic function and thus may contributes to neuronal loss. Our analysis shows that Piccolo is critical for the activity dependent recycling and maintenance of synaptic vesicles (SVs). Specifically, we find that boutons lacking Piccolo have deficits in the Rab5/EEA1 dependent formation of early endosomes and thus the recycling of SVs. Mechanistically, impaired Rab5 function was caused by the reduced synaptic recruitment of Pra1, known to interact selectively with the zinc fingers of Piccolo. Importantly, over-expression of GTPase deficient Rab5 or the Znf1 domain of Piccolo restores the size and recycling of SV pools. These data provide a molecular link between the active zone and endosome sorting at synapses providing hints to how Piccolo contributes to both developmental and psychiatric disorders.Impact StatementThe efficient recycling of synaptic vesicle proteins is critical for the integrity and reliability of synaptic transmission. Increasingly genetic and environmental insults have been shown to affect this recycling pathway, resulting in both cognitive impairment in humans and neurodegenerative diseases, yet the underlying mechanisms are poorly understood. Here we could show that the presynaptic active zone protein Piccolo regulates efficient recycling of synaptic vesicles via Pra1 and Rab5, perhaps explaining why Piccolo loss of function contributes to Pontocerebellar Hypoplasia and major depressive disorders.

scholarly journals Critical role for Piccolo in synaptic vesicle retrieval

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Frauke Ackermann ◽  
Kay Oliver Schink ◽  
Christine Bruns ◽  
Zsuzsanna Izsvák ◽  
F Kent Hamra ◽  
...  
Keyword(s):  
Active Zone ◽  
Synaptic Vesicles ◽  
Critical Role ◽  
Neuronal Loss ◽  
Synaptic Function ◽  
Loss Of Function ◽  
Pontocerebellar Hypoplasia ◽  
Over Expression ◽  
Early Endosomes ◽  
Type 3

Loss of function of the active zone protein Piccolo has recently been linked to a disease, Pontocerebellar Hypoplasia type 3, which causes brain atrophy. Here, we address how Piccolo inactivation in rat neurons adversely affects synaptic function and thus may contribute to neuronal loss. Our analysis shows that Piccolo is critical for the recycling and maintenance of synaptic vesicles. We find that boutons lacking Piccolo have deficits in the Rab5/EEA1 dependent formation of early endosomes and thus the recycling of SVs. Mechanistically, impaired Rab5 function was caused by reduced synaptic recruitment of Pra1, known to interact selectively with the zinc finger domains of Piccolo. Importantly, over-expression of GTPase deficient Rab5 or the Znf1 domain of Piccolo restores the size and recycling of SV pools. These data provide a molecular link between the active zone and endosome sorting at synapses providing hints to how Piccolo contributes to developmental and psychiatric disorders.

Amyloid Precursor Protein Knockout Diminishes Synaptic Vesicle Proteins at the Presynaptic Active Zone in Mouse Brain

2014 ◽  
Vol 11 (10) ◽  
pp. 971-980 ◽  
Author(s):  
Melanie Laßek ◽  
Jens Weingarten ◽  
Amparo Acker-Palmer ◽  
Sandra Bajjalieh ◽  
Ulrike Muller ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Synaptic Vesicle ◽  
Mouse Brain ◽  
Active Zone ◽  
Precursor Protein ◽  
Presynaptic Active Zone ◽  
Vesicle Proteins

Neurotransmitter Release

2017 ◽  
Author(s):  
Peggy Mason
Keyword(s):  
Plasma Membrane ◽  
Synaptic Vesicle ◽  
Active Zone ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Synaptic Cleft ◽  
Fusion Pore ◽  
Synaptic Membrane ◽  
Specialized Region ◽  
Synaptic Vesicle Fusion

The biochemical and physiological processes of neurotransmitter release from an active zone, a specialized region of synaptic membrane, are examined. Synaptic vesicles containing neurotransmitters are docked at the active zone and then primed for release by SNARE complexes that bring them into extreme proximity to the plasma membrane. Entry of calcium ions through voltage-gated calcium channels triggers synaptic vesicle fusion with the synaptic terminal membrane and the consequent diffusion of neurotransmitter into the synaptic cleft. Release results when the fusion pore bridging the synaptic vesicle and plasma membrane widens and neurotransmitter from the inside of the synaptic vesicle diffuses into the synaptic cleft. Membrane from the active zone membrane is endocytosed, and synaptic vesicle proteins are then reassembled into recycled synaptic vesicles, allowing for more rounds of neurotransmitter release.

scholarly journals The CHD Protein, Kismet, is Important for the Recycling of Synaptic Vesicles during Endocytosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nina K. Latcheva ◽  
Taylor L. Delaney ◽  
Jennifer M. Viveiros ◽  
Rachel A. Smith ◽  
Kelsey M. Bernard ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Chromatin Remodeling ◽  
Neurodevelopmental Disorders ◽  
Synaptic Vesicles ◽  
Synaptic Function ◽  
Synaptic Proteins ◽  
Critical Feature ◽  
Synaptic Localization ◽  
Transcription Start Sites ◽  
Mature Neurons

AbstractChromatin remodeling proteins of the chromodomain DNA-binding protein family, CHD7 and CHD8, mediate early neurodevelopmental events including neural migration and differentiation. As such, mutations in either protein can lead to neurodevelopmental disorders. How chromatin remodeling proteins influence the activity of mature synapses, however, is relatively unexplored. A critical feature of mature neurons is well-regulated endocytosis, which is vital for synaptic function to recycle membrane and synaptic proteins enabling the continued release of synaptic vesicles. Here we show that Kismet, the Drosophila homolog of CHD7 and CHD8, regulates endocytosis. Kismet positively influenced transcript levels and bound to dap160 and endophilin B transcription start sites and promoters in whole nervous systems and influenced the synaptic localization of Dynamin/Shibire. In addition, kismet mutants exhibit reduced VGLUT, a synaptic vesicle marker, at stimulated but not resting synapses and reduced levels of synaptic Rab11. Endocytosis is restored at kismet mutant synapses by pharmacologically inhibiting the function of histone deacetyltransferases (HDACs). These data suggest that HDAC activity may oppose Kismet to promote synaptic vesicle endocytosis. A deeper understanding of how CHD proteins regulate the function of mature neurons will help better understand neurodevelopmental disorders.

scholarly journals The proteome of the presynaptic active zone: from docked synaptic vesicles to adhesion molecules and maxi-channels

2009 ◽  
Vol 108 (3) ◽  
pp. 662-675 ◽  
Author(s):  
Marco Morciano ◽  
Tobias Beckhaus ◽  
Michael Karas ◽  
Herbert Zimmermann ◽  
Walter Volknandt
Keyword(s):  
Adhesion Molecules ◽  
Active Zone ◽  
Synaptic Vesicles ◽  
Presynaptic Active Zone

scholarly journals S6 kinase localizes to the presynaptic active zone and functions with PDK1 to control synapse development

2011 ◽  
Vol 194 (6) ◽  
pp. 921-935 ◽  
Author(s):  
Ling Cheng ◽  
Cody Locke ◽  
Graeme W. Davis
Keyword(s):  
Active Zone ◽  
Neurotransmitter Release ◽  
Synaptic Function ◽  
Growth Factor Signaling ◽  
Neuron Type ◽  
S6 Kinase ◽  
Neuronal Dendrites ◽  
Presynaptic Boutons ◽  
Presynaptic Active Zone ◽  
Presynaptic Protein

The dimensions of neuronal dendrites, axons, and synaptic terminals are reproducibly specified for each neuron type, yet it remains unknown how these structures acquire their precise dimensions of length and diameter. Similarly, it remains unknown how active zone number and synaptic strength are specified relative the precise dimensions of presynaptic boutons. In this paper, we demonstrate that S6 kinase (S6K) localizes to the presynaptic active zone. Specifically, S6K colocalizes with the presynaptic protein Bruchpilot (Brp) and requires Brp for active zone localization. We then provide evidence that S6K functions downstream of presynaptic PDK1 to control synaptic bouton size, active zone number, and synaptic function without influencing presynaptic bouton number. We further demonstrate that PDK1 is also a presynaptic protein, though it is distributed more broadly. We present a model in which synaptic S6K responds to local extracellular nutrient and growth factor signaling at the synapse to modulate developmental size specification, including cell size, bouton size, active zone number, and neurotransmitter release.

scholarly journals Trimeric Tau Is Toxic to Human Neuronal Cells at Low Nanomolar Concentrations

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Huilai Tian ◽  
Eliot Davidowitz ◽  
Patricia Lopez ◽  
Sharareh Emadi ◽  
James Moe ◽  
...  
Keyword(s):  
Splice Variants ◽  
Critical Role ◽  
Neuroblastoma Cells ◽  
Neuronal Loss ◽  
Synaptic Function ◽  
Human Neuroblastoma ◽  
Force Microscopy ◽  
Atomic Force ◽  
Therapeutic Development ◽  
Human Neuronal Cells

In Alzheimer’s disease (AD), tau aggregates into fibrils and higher order neurofibrillary tangles, a key histopathological feature of AD. However, soluble oligomeric tau species may play a more critical role in AD progression since these tau species correlate better with neuronal loss and cognitive dysfunction. Recent studies show that extracellular oligomeric tau can inhibit memory formation and synaptic function and also transmit pathology to neighboring neurons. However, the specific forms of oligomeric tau involved in toxicity are still unknown. Here, we used two splice variants of recombinant human tau and generated monomeric, dimeric, and trimeric fractions of each isoform. The composition of each fraction was verified chromatographically and also by atomic force microscopy. The toxicity of each fraction toward both human neuroblastoma cells and cholinergic-like neurons was assessed. Trimeric, but not monomeric or dimeric, tau oligomers of both splice variants were neurotoxic at low nanomolar concentrations. Further characterization of tau oligomer species with disease-specific modifications and morphologies is necessary to identify the best targets for the development of biomarker and therapeutic development for AD and related tauopathies.

scholarly journals Synuclein Regulates Synaptic Vesicle Clustering and Docking at a Vertebrate Synapse

2021 ◽  
Vol 9 ◽  
Author(s):  
Kaitlyn E. Fouke ◽  
M. Elizabeth Wegman ◽  
Sarah A. Weber ◽  
Emily B. Brady ◽  
Cristina Román-Vendrell ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Active Zone ◽  
Synaptic Vesicles ◽  
Significant Loss ◽  
Binding Partner ◽  
Reserve Pool ◽  
Associated Proteins ◽  
Dose Dependent ◽  
Total Membrane ◽  
Synapsin 1

Neurotransmission relies critically on the exocytotic release of neurotransmitters from small synaptic vesicles (SVs) at the active zone. Therefore, it is essential for neurons to maintain an adequate pool of SVs clustered at synapses in order to sustain efficient neurotransmission. It is well established that the phosphoprotein synapsin 1 regulates SV clustering at synapses. Here, we demonstrate that synuclein, another SV-associated protein and synapsin binding partner, also modulates SV clustering at a vertebrate synapse. When acutely introduced to unstimulated lamprey reticulospinal synapses, a pan-synuclein antibody raised against the N-terminal domain of α-synuclein induced a significant loss of SVs at the synapse. Both docked SVs and the distal reserve pool of SVs were depleted, resulting in a loss of total membrane at synapses. In contrast, antibodies against two other abundant SV-associated proteins, synaptic vesicle glycoprotein 2 (SV2) and vesicle-associated membrane protein (VAMP/synaptobrevin), had no effect on the size or distribution of SV clusters. Synuclein perturbation caused a dose-dependent reduction in the number of SVs at synapses. Interestingly, the large SV clusters appeared to disperse into smaller SV clusters, as well as individual SVs. Thus, synuclein regulates clustering of SVs at resting synapses, as well as docking of SVs at the active zone. These findings reveal new roles for synuclein at the synapse and provide critical insights into diseases associated with α-synuclein dysfunction, such as Parkinson’s disease.

scholarly journals Native α-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Jiajie Diao ◽  
Jacqueline Burré ◽  
Sandro Vivona ◽  
Daniel J Cipriano ◽  
Manu Sharma ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Synaptic Vesicles ◽  
Lipid Binding ◽  
Snare Complex ◽  
Loss Of Function ◽  
Related Point ◽  
Molecular Mechanism Of Action ◽  
Presynaptic Protein ◽  
Single Vesicle

α-Synuclein is a presynaptic protein that is implicated in Parkinson's and other neurodegenerative diseases. Physiologically, native α-synuclein promotes presynaptic SNARE-complex assembly, but its molecular mechanism of action remains unknown. Here, we found that native α-synuclein promotes clustering of synaptic-vesicle mimics, using a single-vesicle optical microscopy system. This vesicle-clustering activity was observed for both recombinant and native α-synuclein purified from mouse brain. Clustering was dependent on specific interactions of native α-synuclein with both synaptobrevin-2/VAMP2 and anionic lipids. Out of the three familial Parkinson's disease-related point mutants of α-synuclein, only the lipid-binding deficient mutation A30P disrupted clustering, hinting at a possible loss of function phenotype for this mutant. α-Synuclein had little effect on Ca2+-triggered fusion in our reconstituted single-vesicle system, consistent with in vivo data. α-Synuclein may therefore lead to accumulation of synaptic vesicles at the active zone, providing a ‘buffer’ of synaptic vesicles, without affecting neurotransmitter release itself.

Synaptic Vesicle Distribution and Release at Rat Diaphragm Neuromuscular Junctions

2007 ◽  
Vol 98 (1) ◽  
pp. 478-487 ◽  
Author(s):  
Katharine L. Rowley ◽  
Carlos B. Mantilla ◽  
Leonid G. Ermilov ◽  
Gary C. Sieck
Keyword(s):  
Synaptic Vesicle ◽  
Phrenic Nerve ◽  
Active Zone ◽  
Synaptic Vesicles ◽  
Fiber Type ◽  
Repetitive Stimulation ◽  
Diaphragm Muscle ◽  
Type I ◽  
Fiber Types ◽  
Rat Diaphragm

Synaptic vesicle release at the neuromuscular junction (NMJ) is highly reliable and is vital to the success of synaptic transmission. We examined synaptic vesicle number, distribution, and release at individual type-identified rat diaphragm NMJ. Three-dimensional reconstructions of electron microscopy images were used to obtain novel measurements of active zone distribution and the number of docked synaptic vesicles. Diaphragm muscle-phrenic nerve preparations were used to perform electrophysiological measurements of the decline in quantal content (QC) during repetitive phrenic nerve stimulation. The number of synaptic vesicles available for release vastly exceeds those released with a single stimulus, thus reflecting a relatively low probability of release for individual docked vesicles and at each active zone. There are two components that describe the decline in QC resulting from repetitive stimulation: a rapid phase (<0.5 s) and a delayed phase (<2.5 s). Differences in the initial rapid decline in QC were evident across type-identified presynaptic terminals (fiber type classification based on myosin heavy chain composition). At terminals innervating type IIx and/or IIb fibers, the initial decline in QC during repetitive stimulation matched the predicted depletion of docked synaptic vesicles. In contrast, at terminals innervating type I or IIa fibers, a faster than predicted decline in QC with repetitive stimulation suggests that a decrease in the probability of release at these terminals plays a role in addition to depletion of docked vesicles. Differences in QC decline likely reflect fiber-type specific differences in activation history and correspond with well-described differences in neuromuscular transmission across muscle fiber types.

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