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

Roman Praschberger1, Simon A Lowe2, Nancy T Malintan1

  • 1Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.

Cell Reports
|October 6, 2017
PubMed

Insights

Mutations in the Golgi SNARE protein Membrin cause progressive myoclonus epilepsy. Even subtle defects impair neuronal growth and synaptic function, explaining the neurological disorder.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Mutations in the Golgi SNARE protein Membrin (GOSR2 gene) cause progressive myoclonus epilepsy (PME).
  • Membrin is essential for ER-to-Golgi membrane fusion, but its specific role in neurological disorders is unclear.
  • Understanding how ubiquitous protein defects cause specific nervous system disorders is crucial.

Purpose of the Study:

  • To investigate the molecular and cellular consequences of Membrin mutations.
  • To elucidate the genotype-phenotype relationship in GOSR2-PME.
  • To explore the role of Membrin in neuronal development and function.

Main Methods:

  • Utilized Drosophila models to study GOSR2-PME.
  • Assessed SNARE-mediated membrane fusion efficiency.
  • Analyzed dendritic growth and synaptic structure/function.

Main Results:

  • Pathogenic Membrin mutations cause partial deficits in SNARE-mediated membrane fusion.
  • These fusion defects significantly impair dendritic growth in Drosophila models.
  • Membrin mutations lead to presynaptic cytoskeleton fragmentation, synaptic instability, and hyperactive neurotransmission.

Conclusions:

  • Subtle secretory pathway deficits can profoundly impact neuronal development, specifically dendritic growth.
  • Membrin plays a critical role in maintaining synaptic stability and function.
  • This study provides a mechanistic link between Membrin mutations and the neurological symptoms of GOSR2-PME.
Keywords:
GOSR2GS27Membrindendrite growthprogressive myoclonus epilepsysynaptic integrity

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