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Open AccessArticle

PP1C and PP2A are p70S6K Phosphatases Whose Inhibition Ameliorates HLD12-Associated Inhibition of Oligodendroglial Cell Morphological Differentiation

1
Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
2
Laboratory of Molecular Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan
3
Laboratory of Cell Signaling, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
4
Laboratory of Oncology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
5
Tsumura Research Laboratories, Tsumura & Co., Inashiki, Ibaraki 200-1192, Japan
*
Author to whom correspondence should be addressed.
Biomedicines 2020, 8(4), 89; https://doi.org/10.3390/biomedicines8040089
Received: 7 April 2020 / Accepted: 15 April 2020 / Published: 16 April 2020
(This article belongs to the Section Neurologic Diseases)
Myelin sheaths created by oligodendroglial cells encase neuronal axons to achieve saltatory conduction and protect axons. Pelizaeus-Merzbacher disease (PMD) is a prototypic, hereditary demyelinating oligodendroglial disease of the central nervous system (CNS), and is currently known as hypomyelinating leukodystrophy 1 (HLD1). HLD12 is an autosomal recessive disorder responsible for the gene that encodes vacuolar protein sorting-associated protein 11 homolog (VPS11). VPS11 is a member of the molecular group controlling the early endosome antigen 1 (EEA1)- and Rab7-positive vesicle-mediated protein trafficking to the lysosomal compartments. Herein, we show that the HLD12-associated Cys846-to-Gly (C846G) mutation of VPS11 leads to its aggregate formation with downregulated signaling through 70 kDa S6 protein kinase (p70S6K) in the oligodendroglial cell line FBD-102b as the model. In contrast, wild-type proteins are localized in both EEA1- and Rab7-positive vesicles. Cells harboring the C846G mutant constructs decrease differentiated phenotypes with web-like structures following differentiation, whereas parental cells exhibit them suitably. It is of note that we identify PP1C and PP2A as the protein phosphatases for phosphorylated Thr-389 of p70S6K essential for kinase activation in cells. The respective knockdown experiments or inhibitor treatment stimulates phosphorylation of p70S6K and ameliorates the inhibition of morphological differentiation, as well as the formation of protein aggregates. These results indicate that inhibition of p70S6K phosphatases PP1C and PP2A improves the defective morphological differentiation associated with HLD12 mutation, thereby hinting at amelioration based on a possible molecular and cellular pathological mechanism underlying HLD12. View Full-Text
Keywords: VPS11; HLD12; p70S6K; protein aggregate; oligodendroglial cell; morphological differentiation VPS11; HLD12; p70S6K; protein aggregate; oligodendroglial cell; morphological differentiation
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Matsumoto, N.; Miyamoto, Y.; Hattori, K.; Ito, A.; Harada, H.; Oizumi, H.; Ohbuchi, K.; Mizoguchi, K.; Yamauchi, J. PP1C and PP2A are p70S6K Phosphatases Whose Inhibition Ameliorates HLD12-Associated Inhibition of Oligodendroglial Cell Morphological Differentiation. Biomedicines 2020, 8, 89.

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