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

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

Author information

1
Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan ; Department of Pediatrics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
2
Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan ; Department of Neurology, School of Medicine, Aichi Medical University, 1-1 Yazako Karimata, Nagakute, Aichi 480-1195, Japan.
3
Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
4
Advanced Science Research Laboratories, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
5
Department of Dermatology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
6
Department of Pediatrics, Jichi Medical School, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
7
Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-machi, Kodaira-shi, Tokyo 187-8551, Japan.
8
Center for Induced Pluripotent Stem Cell Research and Application, Graduate School of Medicine, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
9
Center for Medical Genetics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
10
Department of Pediatrics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Erratum in

  • Stem Cell Reports. 2015 Jan 13;4(1):170.

Abstract

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.

PMID:
24936452
PMCID:
PMC4050482
DOI:
10.1016/j.stemcr.2014.03.007
[Indexed for MEDLINE]
Free PMC Article
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