Schwann-Cell-Specific Deletion of Phosphatidylinositol 4-Kinase Alpha Causes Aberrant Myelination.
Schwann-Cell-Specific Deletion of Phosphatidylinositol 4-Kinase Alpha Causes Aberrant Myelination.
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DOI：
10.1016/j.celrep.2018.05.019
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发表时间：
2018-06-05
期刊：
影响因子：
8.8
通讯作者：
Balla T
中科院分区：
文献类型：
--
作者：
Alvarez-Prats A;Bjelobaba I;Aldworth Z;Baba T;Abebe D;Kim YJ;Stojilkovic SS;Stopfer M;Balla T
髓鞘形成过程中主动的膜重塑依赖于磷脂的合成和膜的极化，这两者都依赖于肌醇磷脂。在这里，我们显示在雪旺细胞(SCs)中缺乏磷脂酰肌醇4-激酶α(PI4KA)的小鼠坐骨神经显示髓鞘厚度显著减少，对神经传导性和运动功能造成严重后果。令人惊讶的是，在永生化的小鼠干细胞中，延长PI4KA的抑制时间并没有降低质膜磷脂酰肌醇4，5-二磷酸(PI(4，5)P2)的水平或PI3K的激活，尽管质膜PI4P的水平大幅下降。相反，它引起了肌动蛋白细胞骨架的重排，这种重排也在基因敲除动物的坐骨神经中观察到。PI4KA失活不成比例地降低了突变神经中磷脂酰丝氨酸、磷脂酰乙醇胺和鞘磷脂的含量，在用PI4KA抑制剂处理的干细胞中观察到了类似的变化。这些研究确定了PI4KA在髓鞘形成中的作用，主要影响关键磷脂和肌动蛋白细胞骨架的代谢。Alvarez-Prat等人的研究成果。研究表明，在小鼠中，雪旺细胞(SC)特异性的PI4KA失活会导致周围神经的髓鞘形成缺陷，关键的磷脂髓鞘成分减少，以及肌动蛋白结构的严重变化。结果表明，磷脂和肌动蛋白缺陷是髓鞘缺陷的主要原因。
Active membrane remodeling during myelination relies on phospholipid synthesis and membrane polarization, both of which are known to depend on inositol phospholipids. Here, we show that sciatic nerves of mice lacking phosphatidylinositol 4-kinase alpha (PI4KA) in Schwann cells (SCs) show substantially reduced myelin thickness with grave consequences on nerve conductivity and motor functions. Surprisingly, prolonged inhibition of PI4KA in immortalized mouse SCs failed to decrease plasma membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) levels or PI 3-kinase (PI3K) activation, in spite of large reductions in plasma membrane PI4P levels. Instead, it caused rearrangements of the actin cytoskeleton, which was also observed in sciatic nerves of knockout animals. PI4KA inactivation disproportionally reduced phosphatidylserine, phosphatidylethanolamine, and sphingomyelin content in mutant nerves, with similar changes observed in SCs treated with a PI4KA inhibitor. These studies define a role for PI4KA in myelin formation primarily affecting metabolism of key phospholipids and the actin cytoskeleton. Alvarez-Prats et al. show that Schwann cell (SC)-specific inactivation of PI4KA in mice causes myelination defects in peripheral nerves, decreases in key phospholipid myelin components, and gross alterations in actin architecture. The results point to impaired phospholipid and actin defects as the primary cause of the myelination defects.
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DOI：
10.1083/jcb.201307057
发表时间：
2014-03-31
期刊：
The Journal of cell biology
影响因子：
--
作者：
Heller BA;Ghidinelli M;Voelkl J;Einheber S;Smith R;Grund E;Morahan G;Chandler D;Kalaydjieva L;Giancotti F;King RH;Fejes-Toth AN;Fejes-Toth G;Feltri ML;Lang F;Salzer JL
通讯作者：
Salzer JL
DOI：
10.1126/science.aab1370
发表时间：
2015-07-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chung J;Torta F;Masai K;Lucast L;Czapla H;Tanner LB;Narayanaswamy P;Wenk MR;Nakatsu F;De Camilli P
通讯作者：
De Camilli P
影响因子：
2
作者：
Miyamoto, Yuki;Torii, Tomohiro;Yamauchi, Junji
通讯作者：
Yamauchi, Junji
影响因子：
4.3
作者：
Bogdanik LP;Sleigh JN;Tian C;Samuels ME;Bedard K;Seburn KL;Burgess RW
通讯作者：
Burgess RW
影响因子：
14.5
作者：
Houlden, H;King, RHM;Reilly, MM
通讯作者：
Reilly, MM