Mutations In Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands Of Dendritic Growth And Synaptic Integrity
Simon A. Lowe,
Nancy T. Malintan,
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)
Posted 26 May 2017
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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