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Mutations In Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands Of Dendritic Growth And Synaptic Integrity

By Roman Praschberger, Simon A. Lowe, Nancy T. Malintan, Henry Houlden, Dimitri M Kullmann, Maria M. Usowicz, Shyam S. Krishnakumar, James JL Hodge, James E. Rothman, James E.C. Jepson

Posted 26 May 2017
bioRxiv DOI: 10.1101/142679 (published DOI: 10.1016/j.celrep.2017.09.004)

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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