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Mutations in Membrin/GOSR2 reveal stringent secretory pathway demands of dendritic growth and synaptic integrity

Roman Praschberger, Simon A. Lowe, Nancy T. Malintan, Henry Houlden, Dimitri M. Kullmann, Maria M. Usowicz, Shyam S. Krishnakumar, James J.L. Hodge, James E. Rothman, James E.C. Jepson
doi: https://doi.org/10.1101/142679
Roman Praschberger
1Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
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Simon A. Lowe
2School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
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Nancy T. Malintan
1Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
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Henry Houlden
3Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
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Dimitri M. Kullmann
1Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
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Maria M. Usowicz
2School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
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Shyam S. Krishnakumar
1Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
4Department of Cell Biology, Yale School of Medicine, New Haven, USA
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James J.L. Hodge
2School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
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James E. Rothman
1Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
4Department of Cell Biology, Yale School of Medicine, New Haven, USA
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James E.C. Jepson
1Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
5Lead contact
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  • For correspondence: j.jepson@ucl.ac.uk
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Abstract

Mutations in the Golgi SNARE protein Membrin (encoded by the GOSR2 gene) cause progressive myoclonus epilepsy (PME). Membrin is a ubiquitously important protein mediating ER-to-Golgi membrane fusion, and hence it is unclear how these mutations 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 novel Drosophila models of GOSR2-PME. We also observed axonal trafficking abnormalities in this model, as well as synaptic malformations, trans-synaptic instability and hyperactive synaptic transmission. 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.

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Posted May 26, 2017.
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Mutations in Membrin/GOSR2 reveal stringent secretory pathway demands of dendritic growth and synaptic integrity
Roman Praschberger, Simon A. Lowe, Nancy T. Malintan, Henry Houlden, Dimitri M. Kullmann, Maria M. Usowicz, Shyam S. Krishnakumar, James J.L. Hodge, James E. Rothman, James E.C. Jepson
bioRxiv 142679; doi: https://doi.org/10.1101/142679
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Mutations in Membrin/GOSR2 reveal stringent secretory pathway demands of dendritic growth and synaptic integrity
Roman Praschberger, Simon A. Lowe, Nancy T. Malintan, Henry Houlden, Dimitri M. Kullmann, Maria M. Usowicz, Shyam S. Krishnakumar, James J.L. Hodge, James E. Rothman, James E.C. Jepson
bioRxiv 142679; doi: https://doi.org/10.1101/142679

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