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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:
Journal Article: 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. 2021. "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},
url = {https://www.osti.gov/biblio/1768248}, journal = {Neuron},
issn = {0896-6273},
number = 1,
volume = 109,
place = {United States},
year = {2021},
month = {11}
}

Journal Article:
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