Mutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic Integrity

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Roman Praschberger, Simon A. Lowe, Nancy T. Malintan, Carlo N.G. Giachello, Nian Patel, Henry Houlden, Dimitri M. Kullmann, Richard A. Baines, Maria M. Usowicz, Shyam S. Krishnakumar, James J.L. Hodge, James E. Rothman, James E.C. Jepson
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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Teaser

In this study, Praschberger et al. utilize in vitro assays, patient-derived cells, and Drosophila models to unravel how mutations in the essential Golgi SNARE protein Membrin cause progressive myoclonus epilepsy and to demonstrate a selective vulnerability of developing neurons to partial impairment of ER-to-Golgi trafficking.


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