Journal
CELL REPORTS
Volume 21, Issue 1, Pages 97-109Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.09.004
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Funding
- Wellcome Trust [104033]
- MRC [MR/P012256/1]
- BBSRC [BB/J017221/1, BB/N/014561/1]
- NIHR
- Brain Research Trust PhD studentship
- BBSRC DTP studentship
- BBSRC [BB/J017221/1] Funding Source: UKRI
- MRC [MR/L01095X/1, G116/147, G0801316, MR/P012256/1] Funding Source: UKRI
- Action Medical Research [1725] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/J017221/1] Funding Source: researchfish
- Medical Research Council [MR/P012256/1, G116/147, G0801316, MR/L01095X/1] Funding Source: researchfish
- Muscular Dystrophy UK [16GRO-PS36-0055] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10082] Funding Source: researchfish
- Wellcome Trust [104033/Z/14/Z] Funding Source: researchfish
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Mutations in the Golgi SNARE SNAP [soluble NSF attachment protein] receptor) 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 transsynaptic instability and hyperactive neurotransmission. Our study highlights how dendritic growth is vulnerable even to subtle secretory pathway deficits, uncovers a role for Membrin in synaptic function, and provides a comprehensive explanatory basis for genotype-phenotype relationships in GOSR2-PME.
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