Abstract
SummaryMutations 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.
Highlights
Secreted, membrane, endosomal, and lysosomal proteins are deposited into the endoplasmic reticulum (ER) after ribosomal synthesis
The transport of proteins along this path is facilitated by membrane-enclosed vesicles, and their fusion with the cis-Golgi is mediated by the target (t-) SNARE (SNAP [soluble NSF attachment protein] receptor) proteins Membrin, Sec22b, and Syntaxin-5, in concert with the vesicle (v-) SNARE Bet1 (Parlati et al, 2000; Xu et al, 2000)
Our results suggest a mechanistic basis for the multifaceted neurological features of GOSR2-progressive myoclonus epilepsy (PME) patients, highlight tight trafficking demands of growing dendrites, and illustrate a close-knit dependence of synaptic integrity and neurotransmitter release on cargo trafficking through the Golgi apparatus
Summary
Membrane, endosomal, and lysosomal proteins are deposited into the endoplasmic reticulum (ER) after ribosomal synthesis. Homozygous missense (G144W: layer À3) or compound heterozygous missense and deletion mutations (G144W and K164del: between layer +2 and +3) in the Membrin SNARE motif have recently been shown to cause the severe neurological syndrome progressive myoclonus epilepsy (PME) (Corbett et al, 2011; Praschberger et al, 2015). Patients with this form of PME, termed GOSR2-PME, typically present with ataxia at $3 years of age, followed by cortical myoclonus and generalized tonic-clonic seizures. No paralog is present in the human genome that could functionally replace Membrin in non-neuronal cells and explain the primarily neuronal phenotype
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