PRMT8 as a phospholipase regulates Purkinje cell dendritic arborization and motor coordination.
PRMT8 as a phospholipase regulates Purkinje cell dendritic arborization and motor coordination.
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DOI：
10.1126/sciadv.1500615
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发表时间：
2015-12
期刊：
影响因子：
13.6
通讯作者：
Fukamizu A
中科院分区：
文献类型：
--
作者：
Kim JD;Park KE;Ishida J;Kako K;Hamada J;Kani S;Takeuchi M;Namiki K;Fukui H;Fukuhara S;Hibi M;Kobayashi M;Kanaho Y;Kasuya Y;Mochizuki N;Fukamizu A
PRMT 8直接水解磷脂酰胆碱，这对大脑功能很重要。脊椎动物神经元的发育需要膜磷脂酰胆碱（PC）代谢的变化。虽然PC水解是必不可少的磷脂酶D（PLD）介导的增强轴突生长，PC代谢的决定因素对树突状分支知之甚少。我们表明，蛋白质精氨酸甲基转移酶8（PRMT 8）作为磷脂酶，直接水解PC，产生胆碱和磷脂酸。我们发现PRMT 8敲除小鼠（prmt 8 −/−）表现出异常的运动行为，包括后肢紧握和多动症。此外，prmt 8 −/−小鼠和TALEN诱导的斑马鱼prmt 8突变体和变形体表现出异常的表型，包括浦肯野细胞中树突状树的发育和小脑结构的改变。在prmt 8 −/−小鼠的小脑中，胆碱和乙酰胆碱水平显著降低，而PC水平升高。我们的研究结果表明，PRMT 8既作为精氨酸甲基转移酶，也作为PC水解PLD，这是必要的适当的神经功能。
PRMT8 directly hydrolyzes phosphatidylcholine, which is important for brain functions. The development of vertebrate neurons requires a change in membrane phosphatidylcholine (PC) metabolism. Although PC hydrolysis is essential for enhanced axonal outgrowth mediated by phospholipase D (PLD), less is known about the determinants of PC metabolism on dendritic arborization. We show that protein arginine methyltransferase 8 (PRMT8) acts as a phospholipase that directly hydrolyzes PC, generating choline and phosphatidic acid. We found that PRMT8 knockout mice (prmt8−/−) displayed abnormal motor behaviors, including hindlimb clasping and hyperactivity. Moreover, prmt8−/− mice and TALEN-induced zebrafish prmt8 mutants and morphants showed abnormal phenotypes, including the development of dendritic trees in Purkinje cells and altered cerebellar structure. Choline and acetylcholine levels were significantly decreased, whereas PC levels were increased, in the cerebellum of prmt8−/− mice. Our findings suggest that PRMT8 acts both as an arginine methyltransferase and as a PC-hydrolyzing PLD that is essential for proper neurological functions.