SNAREopathies: Diversity in Mechanisms and Symptoms

Matthijs Verhage; Jakob B. Sørensen

doi:10.1016/j.neuron.2020.05.036

SNAREopathies: Diversity in Mechanisms and Symptoms

Matthijs Verhage^*
, Jakob B. Sørensen

^*Corresponding author for this work

Research output: Contribution to Journal › Review article › Academic › peer-review

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Abstract

Neuronal SNAREs and their key regulators together drive synaptic vesicle exocytosis and synaptic transmission as a single integrated membrane fusion machine. Human pathogenic mutations have now been reported for all eight core components, but patients are diagnosed with very different neurodevelopmental syndromes. We propose to unify these syndromes, based on etiology and mechanism, as “SNAREopathies.” Here, we review the strikingly diverse clinical phenomenology and disease severity and the also remarkably diverse genetic mechanisms. We argue that disease severity generally scales with functional redundancy and, conversely, that the large effect of mutations in some SNARE genes is the price paid for extensive integration and exceptional specialization. Finally, we discuss how subtle differences in components being rate limiting in different types of neurons helps to explain the main symptoms.

Original language	English
Pages (from-to)	22-37
Number of pages	16
Journal	Neuron
Volume	107
Issue number	1
Early online date	18 Jun 2020
DOIs	https://doi.org/10.1016/j.neuron.2020.05.036
Publication status	Published - 8 Jul 2020

Funding

This work was supported by the Lundbeck Foundation ( R277-2018-802 to J.B.S. and M.V.), the Novo Nordisk Foundation ( NNF17OC0028516 to J.B.S.), the Independent Research Fund Denmark ( 8020-00228A to J.B.S.), a European Research Council advanced grant ( 322966 to M.V.), NWO Gravitation Program grant BRAINSCAPES ( NWO 024.004.012 to M.V.), and an MDBR 2019 pilot grant from the Orphan Disease Center ( MDBR-20-136-STXBP1 to M.V.). The authors thank Annemiek van Berkel, Hanna Lammertse, Ruud Toonen, Hilgo Bruining, and Patrick F. Sullivan for critical evaluation of this manuscript and excellent suggestions. The authors acknowledge the strong continuous support from patient families. This work was supported by the Lundbeck Foundation (R277-2018-802 to J.B.S. and M.V.), the Novo Nordisk Foundation (NNF17OC0028516 to J.B.S.), the Independent Research Fund Denmark (8020-00228A to J.B.S.), a European Research Council advanced grant (322966 to M.V.), NWO Gravitation Program grant BRAINSCAPES (NWO 024.004.012 to M.V.), and an MDBR 2019 pilot grant from the Orphan Disease Center (MDBR-20-136-STXBP1 to M.V.). The authors thank Annemiek van Berkel, Hanna Lammertse, Ruud Toonen, Hilgo Bruining, and Patrick F. Sullivan for critical evaluation of this manuscript and excellent suggestions. The authors acknowledge the strong continuous support from patient families. M.V. participates in a holding that owns shares of Sylics (Synaptologics BV), a private company that offers STXBP1 and SNAP25 disease modeling, and has received consulting fees from Sylics.

Funders	Funder number
European Commission
European Research Council
Novo Nordisk Fonden	NNF17OC0028516
NWO	024.004.012
Lundbeckfonden	R277-2018-802
Danmarks Frie Forskningsfond	8020-00228A
Orphan Disease Center, Perelman School of Medicine, University of Pennsylvania	MDBR-20-136-STXBP1
Seventh Framework Programme	322966

Keywords

epilepsy
exocytosis
intellectual disability
membrane fusion
synapse

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10.1016/j.neuron.2020.05.036

SNAREopathies_Diversity in Mechanisms and SymptomsFinal published version, 2.05 MBLicence: Article 25fa Dutch Copyright Act

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SNAREopathies: Diversity in Mechanisms and Symptoms

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