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

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

Research output: Contribution to journalArticle (Academic Journal)peer-review

17 Citations (Scopus)
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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 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 trans-synaptic instability and hyperactive neurotransmission. 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.
Original languageEnglish
Pages (from-to)97-109
Number of pages13
JournalCell Reports
Volume21
Issue number1
Early online date3 Oct 2017
DOIs
Publication statusPublished - 3 Oct 2017

Bibliographical note

01/09/2017

Keywords

  • Membrin
  • GOSR2
  • GS27
  • progressive myoclonus epilepsy
  • dendrite growth
  • synaptic integrity

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