Involvement of ER stress in dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 missense mutations shown by iPSC-derived oligodendrocytes

Stem Cell Reports. 2014 Apr 24;2(5):648-61. doi: 10.1016/j.stemcr.2014.03.007. eCollection 2014 May 6.


Pelizaeus-Merzbacher disease (PMD) is a form of X-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene. Although PLP1 proteins with missense mutations have been shown to accumulate in the rough endoplasmic reticulum (ER) in disease model animals and cell lines transfected with mutant PLP1 genes, the exact pathogenetic mechanism of PMD has not previously been clarified. In this study, we established induced pluripotent stem cells (iPSCs) from two PMD patients carrying missense mutation and differentiated them into oligodendrocytes in vitro. In the PMD iPSC-derived oligodendrocytes, mislocalization of mutant PLP1 proteins to the ER and an association between increased susceptibility to ER stress and increased numbers of apoptotic oligodendrocytes were observed. Moreover, electron microscopic analysis demonstrated drastically reduced myelin formation accompanied by abnormal ER morphology. Thus, this study demonstrates the involvement of ER stress in pathogenic dysmyelination in the oligodendrocytes of PMD patients with the PLP1 missense mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Brain / diagnostic imaging
  • Cell Differentiation
  • Cells, Cultured
  • Endoplasmic Reticulum Stress*
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Infant
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation, Missense
  • Myelin Proteolipid Protein / genetics*
  • Myelin Proteolipid Protein / metabolism
  • Myelin Sheath / metabolism*
  • Oligodendroglia / cytology
  • Oligodendroglia / metabolism*
  • Oligodendroglia / transplantation
  • Pelizaeus-Merzbacher Disease / genetics
  • Pelizaeus-Merzbacher Disease / pathology*
  • Pelizaeus-Merzbacher Disease / therapy
  • Radiography
  • Teratoma / pathology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Young Adult


  • Myelin Proteolipid Protein
  • PLP1 protein, human
  • Transcription Factors