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 |
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Pages (from-to) | 22-37 |
Number of pages | 16 |
Journal | Neuron |
Volume | 107 |
Issue number | 1 |
Early online date | 18 Jun 2020 |
DOIs | |
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.
Funders | Funder number |
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Seventh Framework Programme | 322966 |
Orphan Disease Center, Perelman School of Medicine, University of Pennsylvania | MDBR-20-136-STXBP1 |
European Research Council | |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 024.004.012 |
Lundbeckfonden | R277-2018-802 |
Novo Nordisk Fonden | NNF17OC0028516 |
Danmarks Frie Forskningsfond | 8020-00228A |
Keywords
- epilepsy
- exocytosis
- intellectual disability
- membrane fusion
- synapse