The critical role of membralin in postnatal motor neuron survival and disease

Elife. 2015 May 15;4:e06500. doi: 10.7554/eLife.06500.

Abstract

Hitherto, membralin has been a protein of unknown function. Here, we show that membralin mutant mice manifest a severe and early-onset motor neuron disease in an autosomal recessive manner, dying by postnatal day 5-6. Selective death of lower motor neurons, including those innervating the limbs, intercostal muscles, and diaphragm, is predominantly responsible for this fatal phenotype. Neural expression of a membralin transgene completely rescues membralin mutant mice. Mechanistically, we show that membralin interacts with Erlin2, an endoplasmic reticulum (ER) membrane protein that is located in lipid rafts and known to be important in ER-associated protein degradation (ERAD). Accordingly, the degradation rate of ERAD substrates is attenuated in cells lacking membralin. Membralin mutations or deficiency in mouse models induces ER stress, rendering neurons more vulnerable to cell death. Our study reveals a critical role of membralin in motor neuron survival and suggests a novel mechanism for early-onset motor neuron disease.

Keywords: ER membrane protein; ER stress; motor neuron disease; mouse; neuroscience.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Northern
  • Cell Survival / physiology*
  • DNA Primers / genetics
  • Endoplasmic Reticulum Stress / physiology
  • Endoplasmic Reticulum-Associated Degradation / physiology
  • Genes, Recessive
  • Genetic Vectors / genetics
  • HEK293 Cells
  • Histological Techniques
  • Humans
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Motor Neuron Disease / genetics*
  • Motor Neuron Disease / physiopathology
  • Motor Neurons / physiology*
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism

Substances

  • DNA Primers
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Tmem259 protein, mouse
  • erlin-2 protein, mouse