Impaired eukaryotic translation initiation factor 2B activity specifically in oligodendrocytes reproduces the pathology of vanishing white matter disease in mice

Yifeng Lin, Xiaosha Pang, Guangcun Huang, Stephanie Jamison, Jingye Fang, Heather P. Harding, David Ron, Wensheng Lin

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Vanishing white matter disease (VWMD) is an inherited autosomal-recessive hypomyelinating disease caused by mutations in eukaryotic translation initiation factor 2B (eIF2B). eIF2B mutations predominantly affect the brain white matter, and the characteristic features ofVWMDpathology include myelin loss and foamy oligodendrocytes. Activation of pancreatic endoplasmic reticulum kinase (PERK) has been observed in oligodendrocytes in VWMD. PERK activation in response to endoplasmic reticulum stress attenuates eIF2B activity by phosphorylating eIFα, suggesting that impaired eIF2B activity in oligodendrocytes induced by VWMD mutations or PERK activation exploit similar mechanisms to promote selective white matter pathology in VWMD. Using transgenic mice that allow for temporally controlled activation of PERK specifically in oligodendrocytes, we discovered that strong PERK activation in oligodendrocytes during development suppressed eIF2B activity and reproduced the characteristic features of VWMD in mice, including hypomyelinating phenotype, foamy oligodendrocytes, and myelin loss. Notably, impaired eIF2B activity induced by PERK activation in oligodendrocytes of fully myelinated adult mice had minimal effects on morphology or function. Our observations point to a cell-autonomous role of impaired eIF2B activity in myelinating oligodendrocytes in the pathogenesis of VWMD.

Original languageEnglish (US)
Pages (from-to)12182-12191
Number of pages10
JournalJournal of Neuroscience
Volume34
Issue number36
DOIs
StatePublished - Sep 3 2014

Keywords

  • Eif2B mutations
  • Hypomyelination
  • Oligodendrocyte
  • Pancreatic endoplasmic reticulum kinase
  • Vanishing white matter disease

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