Involvement of ER Stress in Dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 Missense Mutations Shown by iPSC-Derived Oligodendrocytes

• Main Authors: Yuko Numasawa-Kuroiwa, Yohei Okada, Shinsuke Shibata, Noriyuki Kishi, Wado Akamatsu, Masanobu Shoji, Atsushi Nakanishi, Manabu Oyama, Hitoshi Osaka, Ken Inoue, Kazutoshi Takahashi, Shinya Yamanaka, Kenjiro Kosaki, Takao Takahashi, Hideyuki Okano
• Format: Article
• Language: English
• Published: Elsevier 2014-05-01
• Series: Stem Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2213671114000861

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.