Levetiracetam accelerates the onset of supply rate depression in synaptic vesicle trafficking

Epilepsia ◽  
2015 ◽  
Vol 56 (4) ◽  
pp. 535-545 ◽  
Author(s):  
Elizabeth García-Pérez ◽  
Kashif Mahfooz ◽  
João Covita ◽  
Aitor Zandueta ◽  
John F. Wesseling
Keyword(s):  
Synaptic Vesicle ◽  
Vesicle Trafficking ◽  
Supply Rate

scholarly journals Calcium-Dependent Synaptic Vesicle Trafficking Underlies Indefatigable Release at the Hair Cell Afferent Fiber Synapse

Neuron ◽  
2011 ◽  
Vol 70 (2) ◽  
pp. 326-338 ◽  
Author(s):  
Michael E. Schnee ◽  
Joseph Santos-Sacchi ◽  
Manuel Castellano-Muñoz ◽  
Jee-Hyun Kong ◽  
Anthony J. Ricci
Keyword(s):  
Hair Cell ◽  
Synaptic Vesicle ◽  
Vesicle Trafficking ◽  
Afferent Fiber ◽  
Calcium Dependent

Recent Breakthroughs in Neurotransmitter Release: Paradigm for Regulated Exocytosis?

Physiology ◽  
1995 ◽  
Vol 10 (1) ◽  
pp. 42-46
Author(s):  
G Thiel
Keyword(s):  
Synaptic Vesicle ◽  
Brain Function ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Vesicle Trafficking ◽  
Regulated Exocytosis ◽  
Intracellular Vesicle ◽  
Vesicle Cycle ◽  
Synaptic Vesicle Cycle

Synaptic vesicles play a fundamental role in brain function by mediating the release of neurotransmitters. Neurons do not use an entirely unique secretion apparatus but rather a modification of the general secretion machinery. Moreover, the synaptic vesicle cycle has many similarities with intracellular vesicle trafficking pathways.

scholarly journals TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model

Brain ◽  
2019 ◽  
Vol 142 (8) ◽  
pp. 2319-2335 ◽  
Author(s):  
Kevin Lüthy ◽  
Davide Mei ◽  
Baptiste Fischer ◽  
Maurizio De Fusco ◽  
Jef Swerts ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Vesicle Trafficking ◽  
Disease Model ◽  
Stress Sensitivity ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Rolandic Epilepsy ◽  
Compound Heterozygous Mutations ◽  
Exercise Induced

AbstractGenetic mutations in TBC1D24 have been associated with multiple phenotypes, with epilepsy being the main clinical manifestation. The TBC1D24 protein consists of the unique association of a Tre2/Bub2/Cdc16 (TBC) domain and a TBC/lysin motif domain/catalytic (TLDc) domain. More than 50 missense and loss-of-function mutations have been described and are spread over the entire protein. Through whole genome/exome sequencing we identified compound heterozygous mutations, R360H and G501R, within the TLDc domain, in an index family with a Rolandic epilepsy exercise-induced dystonia phenotype (http://omim.org/entry/608105). A 20-year long clinical follow-up revealed that epilepsy was self-limited in all three affected patients, but exercise-induced dystonia persisted into adulthood in two. Furthermore, we identified three additional sporadic paediatric patients with a remarkably similar phenotype, two of whom had compound heterozygous mutations consisting of an in-frame deletion I81_K84 and an A500V mutation, and the third carried T182M and G511R missense mutations, overall revealing that all six patients harbour a missense mutation in the subdomain of TLDc between residues 500 and 511. We solved the crystal structure of the conserved Drosophila TLDc domain. This allowed us to predict destabilizing effects of the G501R and G511R mutations and, to a lesser degree, of R360H and potentially A500V. Next, we characterized the functional consequences of a strong and a weak TLDc mutation (TBC1D24G501R and TBC1D24R360H) using Drosophila, where TBC1D24/Skywalker regulates synaptic vesicle trafficking. In a Drosophila model neuronally expressing human TBC1D24, we demonstrated that the TBC1D24G501R TLDc mutation causes activity-induced locomotion and synaptic vesicle trafficking defects, while TBC1D24R360H is benign. The neuronal phenotypes of the TBC1D24G501R mutation are consistent with exacerbated oxidative stress sensitivity, which is rescued by treating TBC1D24G501R mutant animals with antioxidants N-acetylcysteine amide or α-tocopherol as indicated by restored synaptic vesicle trafficking levels and sustained behavioural activity. Our data thus show that mutations in the TLDc domain of TBC1D24 cause Rolandic-type focal motor epilepsy and exercise-induced dystonia. The humanized TBC1D24G501R fly model exhibits sustained activity and vesicle transport defects. We propose that the TBC1D24/Sky TLDc domain is a reactive oxygen species sensor mediating synaptic vesicle trafficking rates that, when dysfunctional, causes a movement disorder in patients and flies. The TLDc and TBC domain mutations’ response to antioxidant treatment we observed in the animal model suggests a potential for combining antioxidant-based therapeutic approaches to TBC1D24-associated disorders with previously described lipid-altering strategies for TBC domain mutations.

scholarly journals APache Is an AP2-Interacting Protein Involved in Synaptic Vesicle Trafficking and Neuronal Development

Cell Reports ◽  
2017 ◽  
Vol 21 (12) ◽  
pp. 3596-3611 ◽  
Author(s):  
Alessandra Piccini ◽  
Enrico Castroflorio ◽  
Pierluigi Valente ◽  
Fabrizia C. Guarnieri ◽  
Davide Aprile ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Neuronal Development ◽  
Vesicle Trafficking ◽  
Interacting Protein

scholarly journals A New Kinetic Framework for Synaptic Vesicle Trafficking Tested in Synapsin Knock-Outs

2011 ◽  
Vol 31 (32) ◽  
pp. 11563-11577 ◽  
Author(s):  
T. Gabriel ◽  
E. Garcia-Perez ◽  
K. Mahfooz ◽  
J. Goni ◽  
R. Martinez-Turrillas ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Vesicle Trafficking

scholarly journals Functional Role of ATP Binding to Synapsin I In Synaptic Vesicle Trafficking and Release Dynamics

2014 ◽  
Vol 34 (44) ◽  
pp. 14752-14768 ◽  
Author(s):  
M. Orlando ◽  
G. Lignani ◽  
L. Maragliano ◽  
A. Fassio ◽  
F. Onofri ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Functional Role ◽  
Vesicle Trafficking ◽  
Synapsin I ◽  
Atp Binding

scholarly journals Hypothesis Relating the Structure, Biochemistry and Function of Active Zone Material Macromolecules at a Neuromuscular Junction

2022 ◽  
Vol 13 ◽  
Author(s):  
Joseph A. Szule
Keyword(s):  
Membrane Fusion ◽  
Synaptic Vesicle ◽  
Active Zone ◽  
Structural Integrity ◽  
Neuromuscular Junctions ◽  
Vesicle Trafficking ◽  
Material Structure ◽  
Neurotransmitter Secretion ◽  
Active Zones ◽  
And Function

This report integrates knowledge of in situ macromolecular structures and synaptic protein biochemistry to propose a unified hypothesis for the regulation of certain vesicle trafficking events (i.e., docking, priming, Ca2+-triggering, and membrane fusion) that lead to neurotransmitter secretion from specialized “active zones” of presynaptic axon terminals. Advancements in electron tomography, to image tissue sections in 3D at nanometer scale resolution, have led to structural characterizations of a network of different classes of macromolecules at the active zone, called “Active Zone Material’. At frog neuromuscular junctions, the classes of Active Zone Material macromolecules “top-masts”, “booms”, “spars”, “ribs” and “pins” direct synaptic vesicle docking while “pins”, “ribs” and “pegs” regulate priming to influence Ca2+-triggering and membrane fusion. Other classes, “beams”, “steps”, “masts”, and “synaptic vesicle luminal filaments’ likely help organize and maintain the structural integrity of active zones. Extensive studies on the biochemistry that regulates secretion have led to comprehensive characterizations of the many conserved proteins universally involved in these trafficking events. Here, a hypothesis including a partial proteomic atlas of Active Zone Material is presented which considers the common roles, binding partners, physical features/structure, and relative positioning in the axon terminal of both the proteins and classes of macromolecules involved in the vesicle trafficking events. The hypothesis designates voltage-gated Ca2+ channels and Ca2+-gated K+ channels to ribs and pegs that are connected to macromolecules that span the presynaptic membrane at the active zone. SNARE proteins (Syntaxin, SNAP25, and Synaptobrevin), SNARE-interacting proteins Synaptotagmin, Munc13, Munc18, Complexin, and NSF are designated to ribs and/or pins. Rab3A and Rabphillin-3A are designated to top-masts and/or booms and/or spars. RIM, Bassoon, and Piccolo are designated to beams, steps, masts, ribs, spars, booms, and top-masts. Spectrin is designated to beams. Lastly, the luminal portions of SV2 are thought to form the bulk of the observed synaptic vesicle luminal filaments. The goal here is to help direct future studies that aim to bridge Active Zone Material structure, biochemistry, and function to ultimately determine how it regulates the trafficking events in vivo that lead to neurotransmitter secretion.

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