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Title: Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies

Abstract

SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complex, composed of synaptobrevin, syntaxin, and SNAP25, forms the essential fusion machinery for neurotransmitter release. Recent studies have reported several mutations in the gene encoding SNAP25 as a causative factor for developmental and epileptic encephalopathies of infancy and childhood with diverse clinical manifestations. However, it remains unclear how SNAP25 mutations give rise to these disorders. In this work, we show that although structurally clustered mutations in SNAP25 give rise to related synaptic transmission phenotypes, specific alterations in spontaneous neurotransmitter release are a key factor to account for disease heterogeneity. Importantly, we identified a single mutation that augments spontaneous release without altering evoked release, suggesting that aberrant spontaneous release is sufficient to cause disease in humans.

Authors:
ORCiD logo [1];  [1];  [1]; ORCiD logo [2];  [1]; ORCiD logo [2];  [1];  [3];  [1]; ORCiD logo [2];  [1]
  1. Vanderbilt Univ., Nashville, TN (United States)
  2. Stanford Univ., CA (United States)
  3. Columbia Univ., New York, NY (United States)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
OSTI Identifier:
1768248
Grant/Contract Number:  
AC02-76SF00515; R01MH081060; K99MH113764; R37MH63105; R01AG055577; R01MH070727; R00MH113764; R01MH66198; P41GM103393
Resource Type:
Accepted Manuscript
Journal Name:
Neuron
Additional Journal Information:
Journal Volume: 109; Journal Issue: 1; Journal ID: ISSN 0896-6273
Publisher:
Cell Press - Elsevier
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; SNAP25; spontaneous release; neurotransmitter; synaptic transmission; exocytosis; synaptotagmin; epilepsy; development; developmental delay; child neurology

Citation Formats

Alten, Baris, Zhou, Qiangjun, Shin, Ok-Ho, Esquivies, Luis, Lin, Pei-Yi, White, K. Ian, Sun, Rong, Chung, Wendy K., Monteggia, Lisa M., Brunger, Axel T., and Kavalali, Ege T. Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies. United States: N. p., 2021. Web. doi:10.1016/j.neuron.2020.10.012.
Alten, Baris, Zhou, Qiangjun, Shin, Ok-Ho, Esquivies, Luis, Lin, Pei-Yi, White, K. Ian, Sun, Rong, Chung, Wendy K., Monteggia, Lisa M., Brunger, Axel T., & Kavalali, Ege T. Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies. United States. https://doi.org/10.1016/j.neuron.2020.10.012
Alten, Baris, Zhou, Qiangjun, Shin, Ok-Ho, Esquivies, Luis, Lin, Pei-Yi, White, K. Ian, Sun, Rong, Chung, Wendy K., Monteggia, Lisa M., Brunger, Axel T., and Kavalali, Ege T. Wed . "Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies". United States. https://doi.org/10.1016/j.neuron.2020.10.012.
@article{osti_1768248,
title = {Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies},
author = {Alten, Baris and Zhou, Qiangjun and Shin, Ok-Ho and Esquivies, Luis and Lin, Pei-Yi and White, K. Ian and Sun, Rong and Chung, Wendy K. and Monteggia, Lisa M. and Brunger, Axel T. and Kavalali, Ege T.},
abstractNote = {SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complex, composed of synaptobrevin, syntaxin, and SNAP25, forms the essential fusion machinery for neurotransmitter release. Recent studies have reported several mutations in the gene encoding SNAP25 as a causative factor for developmental and epileptic encephalopathies of infancy and childhood with diverse clinical manifestations. However, it remains unclear how SNAP25 mutations give rise to these disorders. In this work, we show that although structurally clustered mutations in SNAP25 give rise to related synaptic transmission phenotypes, specific alterations in spontaneous neurotransmitter release are a key factor to account for disease heterogeneity. Importantly, we identified a single mutation that augments spontaneous release without altering evoked release, suggesting that aberrant spontaneous release is sufficient to cause disease in humans.},
doi = {10.1016/j.neuron.2020.10.012},
journal = {Neuron},
number = 1,
volume = 109,
place = {United States},
year = {2021},
month = {11}
}

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Works referenced in this record:

Synaptotagmin: a calcium sensor on the synaptic vesicle surface
journal, May 1992


A Third-Generation Lentivirus Vector with a Conditional Packaging System
journal, November 1998


SNAREopathies: Diversity in Mechanisms and Symptoms
journal, July 2020


Age at onset of epilepsy, pharmacoresistance, and cognitive outcomes: A prospective cohort study
journal, September 2012


Synaptotagmin-1 and -7 Are Redundantly Essential for Maintaining the Capacity of the Readily-Releasable Pool of Synaptic Vesicles
journal, October 2015


Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 Å resolution
journal, September 1998

  • Sutton, R. Bryan; Fasshauer, Dirk; Jahn, Reinhard
  • Nature, Vol. 395, Issue 6700
  • DOI: 10.1038/26412

Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis
journal, August 2015

  • Zhou, Qiangjun; Lai, Ying; Bacaj, Taulant
  • Nature, Vol. 525, Issue 7567
  • DOI: 10.1038/nature14975

Overcoming presynaptic effects of VAMP2 mutations with 4‐aminopyridine treatment
journal, October 2020

  • Simmons, Roxanne L.; Li, Haiyan; Alten, Baris
  • Human Mutation, Vol. 41, Issue 11
  • DOI: 10.1002/humu.24109

Large-scale discovery of novel genetic causes of developmental disorders
journal, December 2014


De Novo Mutations in the Sodium-Channel Gene SCN1A Cause Severe Myoclonic Epilepsy of Infancy
journal, June 2001

  • Claes, Lieve; Del-Favero, Jurgen; Ceulemans, Berten
  • The American Journal of Human Genetics, Vol. 68, Issue 6
  • DOI: 10.1086/320609

De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
journal, October 2014

  • Appenzeller, Silke; Balling, Rudi; Barisic, Nina
  • The American Journal of Human Genetics, Vol. 95, Issue 4
  • DOI: 10.1016/j.ajhg.2014.08.013

Intellicount : High-Throughput Quantification of Fluorescent Synaptic Protein Puncta by Machine Learning
journal, November 2017


A novel missense SNAP25b mutation in two affected siblings from an Israeli family showing seizures and cerebellar ataxia
journal, February 2018


The genetic landscape of the epileptic encephalopathies of infancy and childhood
journal, March 2016


SNAP receptors implicated in vesicle targeting and fusion
journal, March 1993

  • Söllner, Thomas; Whiteheart, Sidney W.; Brunner, Michael
  • Nature, Vol. 362, Issue 6418
  • DOI: 10.1038/362318a0

Differential Effects of SNAP-25 Deletion on Ca 2+ -Dependent and Ca 2+ -Independent Neurotransmission
journal, August 2007

  • Bronk, Peter; Deák, Ferenc; Wilson, Michael C.
  • Journal of Neurophysiology, Vol. 98, Issue 2
  • DOI: 10.1152/jn.00226.2007

Lentivirus-delivered stable gene silencing by RNAi in primary cells
journal, April 2003


Monitoring synaptic transmission in primary neuronal cultures using local extracellular stimulation
journal, March 2007


PHENIX : building new software for automated crystallographic structure determination
journal, October 2002

  • Adams, Paul D.; Grosse-Kunstleve, Ralf W.; Hung, Li-Wei
  • Acta Crystallographica Section D Biological Crystallography, Vol. 58, Issue 11
  • DOI: 10.1107/S0907444902016657

Ca2+-Dependent Synaptotagmin Binding to SNAP-25 Is Essential for Ca2+-Triggered Exocytosis
journal, May 2002


Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets
journal, March 2017


Excitatory and Inhibitory Neurons Utilize Different Ca2+ Sensors and Sources to Regulate Spontaneous Release
journal, June 2018


Differential expression of SNAP-25 protein isoforms during divergent vesicle fusion events of neural development.
journal, February 1995

  • Bark, I. C.; Hahn, K. M.; Ryabinin, A. E.
  • Proceedings of the National Academy of Sciences, Vol. 92, Issue 5
  • DOI: 10.1073/pnas.92.5.1510

Mutation in SNAP25 as a novel genetic cause of epilepsy and intellectual disability
journal, January 2013

  • Rohena, Luis; Neidich, Julie; Truitt Cho, Megan
  • Rare Diseases, Vol. 1, Issue 1
  • DOI: 10.4161/rdis.26314

Synaptotagmin I functions as a calcium regulator of release probability
journal, March 2001

  • Fernández-Chacón, Rafael; Königstorfer, Andreas; Gerber, Stefan H.
  • Nature, Vol. 410, Issue 6824
  • DOI: 10.1038/35065004

Definition of the Readily Releasable Pool of Vesicles at Hippocampal Synapses
journal, June 1996


SYT1-associated neurodevelopmental disorder: a case series
journal, August 2018


Epilepsy-causing STX1B mutations translate altered protein functions into distinct phenotypes in mouse neurons
journal, June 2020

  • Vardar, Gülçin; Gerth, Fabian; Schmitt, Xiao Jakob
  • Brain, Vol. 143, Issue 7
  • DOI: 10.1093/brain/awaa151

Common intermediates and kinetics, but different energetics, in the assembly of SNARE proteins
journal, September 2014


DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources
journal, April 2009

  • Firth, Helen V.; Richards, Shola M.; Bevan, A. Paul
  • The American Journal of Human Genetics, Vol. 84, Issue 4
  • DOI: 10.1016/j.ajhg.2009.03.010

The hidden genetics of epilepsy—a clinically important new paradigm
journal, April 2014


Synaptotagmin-1 functions as a Ca2+ sensor for spontaneous release
journal, May 2009

  • Xu, Jun; Pang, Zhiping P.; Shin, Ok-Ho
  • Nature Neuroscience, Vol. 12, Issue 6
  • DOI: 10.1038/nn.2320

Human cDNA clones encoding two different isoforms of the nerve terminal protein SNAP-25
journal, February 1994


Molecular Basis for Synaptotagmin-1-Associated Neurodevelopmental Disorder
journal, July 2020


Targeting Homeostatic Synaptic Plasticity for Treatment of Mood Disorders
journal, June 2020


Genetic ablation of the t-SNARE SNAP-25 distinguishes mechanisms of neuroexocytosis
journal, December 2001

  • Washbourne, Philip; Thompson, Peter M.; Carta, Mario
  • Nature Neuroscience, Vol. 5, Issue 1
  • DOI: 10.1038/nn783

The mechanisms and functions of spontaneous neurotransmitter release
journal, December 2014

  • Kavalali, Ege T.
  • Nature Reviews Neuroscience, Vol. 16, Issue 1
  • DOI: 10.1038/nrn3875

The role of proline residues in the dynamics of transmembrane helices: the case of bacteriorhodopsin
journal, January 2006

  • Perálvarez-Marín, Alex; Bourdelande, José-Luis; Querol, Enric
  • Molecular Membrane Biology, Vol. 23, Issue 2
  • DOI: 10.1080/09687860500435019

Regional and developmental brain expression patterns of SNAP25 splice variants
journal, April 2011


SNAREpins: Minimal Machinery for Membrane Fusion
journal, March 1998


Synaptotagmin I: A major Ca2+ sensor for transmitter release at a central synapse
journal, November 1994


High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies
journal, November 2017

  • Hamdan, Fadi F.; Myers, Candace T.; Cossette, Patrick
  • The American Journal of Human Genetics, Vol. 101, Issue 5
  • DOI: 10.1016/j.ajhg.2017.09.008

HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes
journal, July 2006

  • Minor, Wladek; Cymborowski, Marcin; Otwinowski, Zbyszek
  • Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 8
  • DOI: 10.1107/S0907444906019949

Synaptotagmin-1 and Synaptotagmin-7 Trigger Synchronous and Asynchronous Phases of Neurotransmitter Release
journal, November 2013


MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009

  • Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
  • DOI: 10.1107/S0907444909042073

Coot model-building tools for molecular graphics
journal, November 2004

  • Emsley, Paul; Cowtan, Kevin
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
  • DOI: 10.1107/S0907444904019158

Sequential N- to C-terminal SNARE complex assembly drives priming and fusion of secretory vesicles
journal, February 2006

  • Sørensen, Jakob B.; Wiederhold, Katrin; Müller, Emil M.
  • The EMBO Journal, Vol. 25, Issue 5
  • DOI: 10.1038/sj.emboj.7601003

A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion
journal, November 1993


Protein production by auto-induction in high-density shaking cultures
journal, May 2005


Molecular Mechanisms of Synaptic Vesicle Priming by Munc13 and Munc18
journal, August 2017


Epileptiform Activity and Cognitive Deficits in SNAP-25+/− Mice are Normalized by Antiepileptic Drugs
journal, October 2012

  • Corradini, Irene; Donzelli, Andrea; Antonucci, Flavia
  • Cerebral Cortex, Vol. 24, Issue 2
  • DOI: 10.1093/cercor/bhs316

De novo variants in neurodevelopmental disorders with epilepsy
journal, June 2018


Behavioral Analysis of SNAP-25 and Synaptobrevin-2 Haploinsufficiency in Mice
journal, November 2019


The primed SNARE–complexin–synaptotagmin complex for neuronal exocytosis
journal, August 2017

  • Zhou, Qiangjun; Zhou, Peng; Wang, Austin L.
  • Nature, Vol. 548, Issue 7668
  • DOI: 10.1038/nature23484

Cell-Specific Loss of SNAP25 from Cortical Projection Neurons Allows Normal Development but Causes Subsequent Neurodegeneration
journal, May 2018

  • Hoerder-Suabedissen, Anna; Korrell, Kim V.; Hayashi, Shuichi
  • Cerebral Cortex, Vol. 29, Issue 5
  • DOI: 10.1093/cercor/bhy127

Prevalence and architecture of de novo mutations in developmental disorders
journal, January 2017


ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology
journal, March 2017

  • Scheffer, Ingrid E.; Berkovic, Samuel; Capovilla, Giuseppe
  • Epilepsia, Vol. 58, Issue 4
  • DOI: 10.1111/epi.13709

Munc18-1-regulated stage-wise SNARE assembly underlying synaptic exocytosis
journal, December 2015


Single Reconstituted Neuronal SNARE Complexes Zipper in Three Distinct Stages
journal, August 2012


Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability
journal, November 2014


Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment
journal, April 2019

  • Salpietro, Vincenzo; Malintan, Nancy T.; Llano-Rivas, Isabel
  • The American Journal of Human Genetics, Vol. 104, Issue 4
  • DOI: 10.1016/j.ajhg.2019.02.016

A synaptotagmin suppressor screen indicates SNARE binding controls the timing and Ca2+ cooperativity of vesicle fusion
journal, September 2017