An Epilepsy-Associated SV2A Mutation Disrupts Synaptotagmin-1 Expression and Activity-Dependent Trafficking Article Swipe
Callista B. Harper
,
Christopher Small
,
Elizabeth C. Davenport
,
Darryl W. Low
,
Karen J. Smillie
,
Ramón Martínez‐Mármol
,
Frédéric A. Meunier
,
Michael A. Cousin
·
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.1523/jneurosci.0210-20.2020
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.1523/jneurosci.0210-20.2020
The epilepsy-linked gene SV2A , has a number of potential roles in the synaptic vesicle (SV) life cycle. However, how loss of SV2A function translates into presynaptic dysfunction and ultimately seizure activity is still undetermined. In this study, we examined whether the first SV2A mutation identified in human disease (R383Q) could provide information regarding which SV2A-dependent events are critical in the translation to epilepsy. We utilized a molecular replacement strategy in which exogenous SV2A was expressed in mouse neuronal cultures of either sex, which had been depleted of endogenous SV2A to mimic the homozygous human condition. We found that the R383Q mutation resulted in a mislocalization of SV2A from SVs to the plasma membrane, but had no effect on its activity-dependent trafficking. This SV2A mutant displayed reduced mobility when stranded on the plasma membrane and reduced binding to its interaction partner synaptotagmin-1 (Syt1). Furthermore, the R383Q mutant failed to rescue reduced expression and dysfunctional activity-dependent trafficking of Syt1 in the absence of endogenous SV2A. This suggests that the inability to control Syt1 expression and trafficking at the presynapse may be key in the transition from loss of SV2A function to seizure activity. SIGNIFICANCE STATEMENT SV2A is a synaptic vesicle (SV) protein, the absence or dysfunction of which is linked to epilepsy. However, the series of molecular events that result in this neurological disorder is still undetermined. We demonstrate here that the first human mutation in SV2A identified in an individual with epilepsy displays reduced binding to synaptotagmin-1 (Syt1), an SV protein essential for synchronous neurotransmitter release. Furthermore, this mutant cannot correct alterations in both Syt1 expression and trafficking when expressed in the absence of endogenous SV2A (to mimic the homozygous human condition). This suggests that the inability to control Syt1 expression and trafficking may be key in the transition from loss of SV2A function to seizure activity.
Related Topics
Concepts
Synaptotagmin 1
Mutation
Biology
Synaptotagmin I
Synaptic vesicle
Neurotransmission
Cell biology
Mutant
Neuroscience
Genetics
Vesicle
Gene
Receptor
Membrane
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1523/jneurosci.0210-20.2020
- https://www.jneurosci.org/content/jneuro/40/23/4586.full.pdf
- OA Status
- bronze
- Cited By
- 41
- References
- 43
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W3019039305
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W3019039305Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1523/jneurosci.0210-20.2020Digital Object Identifier
- Title
-
An Epilepsy-Associated SV2A Mutation Disrupts Synaptotagmin-1 Expression and Activity-Dependent TraffickingWork title
- Type
-
articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2020Year of publication
- Publication date
-
2020-04-27Full publication date if available
- Authors
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Callista B. Harper, Christopher Small, Elizabeth C. Davenport, Darryl W. Low, Karen J. Smillie, Ramón Martínez‐Mármol, Frédéric A. Meunier, Michael A. CousinList of authors in order
- Landing page
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https://doi.org/10.1523/jneurosci.0210-20.2020Publisher landing page
- PDF URL
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https://www.jneurosci.org/content/jneuro/40/23/4586.full.pdfDirect link to full text PDF
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YesWhether a free full text is available
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bronzeOpen access status per OpenAlex
- OA URL
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https://www.jneurosci.org/content/jneuro/40/23/4586.full.pdfDirect OA link when available
- Concepts
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Synaptotagmin 1, Mutation, Biology, Synaptotagmin I, Synaptic vesicle, Neurotransmission, Cell biology, Mutant, Neuroscience, Genetics, Vesicle, Gene, Receptor, MembraneTop concepts (fields/topics) attached by OpenAlex
- Cited by
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41Total citation count in OpenAlex
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2025: 4, 2024: 9, 2023: 7, 2022: 10, 2021: 9Per-year citation counts (last 5 years)
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43Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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