Projects per year
Abstract
Mutations in the Golgi SNARE protein Membrin (encoded by the GOSR2 gene) cause progressive myoclonus epilepsy (PME). Membrin is a ubiquitous and essential protein mediating ER-to-Golgi membrane fusion. Thus, it is unclear how mutations in Membrin result in a disorder restricted to the nervous system. Here we use a multi-layered strategy to elucidate the consequences of Membrin mutations from protein to neuron. We show that the pathogenic mutations cause partial reductions in SNARE-mediated membrane fusion. Importantly, these alterations were sufficient to profoundly impair dendritic growth in Drosophila models of GOSR2-PME. Furthermore, we show that Membrin mutations cause fragmentation of the presynaptic cytoskeleton coupled with trans-synaptic instability and hyperactive neurotransmission. Our study highlights how dendritic growth is vulnerable even to subtle secretory pathway deficits, uncovers a previously uncharacterized role for Membrin in synaptic function, and provides a comprehensive explanatory basis for genotype-phenotype relationships in GOSR2-PME.
Original language | English |
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Pages (from-to) | 97-109 |
Number of pages | 13 |
Journal | Cell Reports |
Volume | 21 |
Issue number | 1 |
Early online date | 3 Oct 2017 |
DOIs | |
Publication status | Published - 3 Oct 2017 |
Bibliographical note
01/09/2017Keywords
- Membrin
- GOSR2
- GS27
- progressive myoclonus epilepsy
- dendrite growth
- synaptic integrity
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Dive into the research topics of 'Mutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic Integrity'. Together they form a unique fingerprint.Projects
- 1 Finished
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How does light control the activity and electrical properties of neurons integrating arousal behaviour, circadian rhythms, and sleep?
Hodge, J. J. L. (Principal Investigator)
1/01/13 → 1/04/16
Project: Research
Profiles
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Professor James J L Hodge
- School of Physiology, Pharmacology & Neuroscience - Professor
- Dynamic Cell Biology
- Bristol Neuroscience
Person: Academic , Member