PP1C and PP2A are p70S6K Phosphatases Whose Inhibition Ameliorates HLD12-Associated Inhibition of Oligodendroglial Cell Morphological Differentiation
PP1C and PP2A are p70S6K Phosphatases Whose Inhibition Ameliorates HLD12-Associated Inhibition of Oligodendroglial Cell Morphological Differentiation
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DOI：
10.3390/biomedicines8040089
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发表时间：
2020-04-01
期刊：
影响因子：
4.7
通讯作者：
Yamauchi, Junji
中科院分区：
文献类型：
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作者：
Matsumoto, Naoto;Miyamoto, Yuki;Yamauchi, Junji
由少突胶质细胞产生的髓鞘包裹神经元轴突以实现跳跃式传导并保护轴突。Pelizaeus-Merzbacher病（PMD）是中枢神经系统（CNS）的典型遗传性脱髓鞘少突胶质细胞疾病，并且目前被称为低髓鞘化脑白质营养不良1（HLD 1）。HLD 12是一种常染色体隐性遗传疾病，其基因编码液泡蛋白分选相关蛋白11同源物（VPS 11）。VPS 11是控制早期内体抗原1（EEA 1）和Rab 7阳性囊泡介导的蛋白运输到溶酶体区室的分子组的成员。在此，我们表明，HLD 12相关的Cys 846-到-Gly（C846 G）突变的VPS 11导致其聚集体的形成与下调信号通过70 kDa的S6蛋白激酶（p70 S6 K）在少突胶质细胞系FBD-102 b作为模型。相反，野生型蛋白定位于EEA 1和Rab 7阳性囊泡。携带C846 G突变体构建体的细胞在分化后减少具有网状结构的分化表型，而亲本细胞适当地表现出它们。值得注意的是，我们鉴定PP 1C和PP 2A为细胞中激酶活化所必需的p70 S6 K磷酸化Thr-389的蛋白磷酸酶。相应的敲低实验或抑制剂处理刺激p70 S6 K的磷酸化并改善形态分化的抑制以及蛋白质聚集体的形成。这些结果表明，抑制p70 S6 K磷酸酶PP 1C和PP 2A改善了与HLD 12突变相关的缺陷形态分化，从而暗示了基于HLD 12潜在的可能分子和细胞病理机制的改善。
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.