PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS
PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS
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PI 3-激酶 delta 增强轴突 PIP3 以支持成人中枢神经系统的轴突再生
DOI：
10.1101/787994
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Barber A
中科院分区：
文献类型：
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作者：
Barber A
周围神经系统（PNS）神经元支持轴突再生到成年，而中枢神经系统（CNS）神经元在发育后失去再生能力。为了更好地理解这种下降，同时旨在改善再生，我们专注于磷酸肌醇3-激酶（PI 3 K）及其产物磷脂酰肌醇（3，4，5）-三磷酸（PIP 3）。我们发现神经元PIP 3随着成熟而降低，与再生能力一致，首先在细胞体中，随后在轴突中。我们发现，成年PNS神经元利用PI 3 K的两个催化亚基进行有效的再生：p110α和p110δ。p110α在CNS神经元中的过表达没有影响，然而，p110δ的表达恢复了轴突PIP 3，并增强了大鼠和人类神经元以及转基因小鼠的CNS再生，其功能与p110α的过度活化H1047 R突变相同。此外，p110δ的病毒递送促进视神经损伤后的稳健再生。这些发现表明轴突PIP 3的缺陷是内源性再生失败的原因，并表明天然p110δ通过以过度活跃的方式发挥作用而促进轴突再生。
Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol(3,4,5)-trisphosphate (PIP3). We found that neuronal PIP3 decreases with maturity in line with regenerative competence, firstly in the cell body and subsequently in the axon. We show that adult PNS neurons utilise two catalytic subunits of PI3K for efficient regeneration: p110α and p110δ. Overexpressing p110α in CNS neurons had no effect, however expression of p110δ restored axonal PIP3 and enhanced CNS regeneration in rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110α. Furthermore, viral delivery of p110δ promoted robust regeneration after optic nerve injury. These findings demonstrate a deficit of axonal PIP3 as a reason for intrinsic regeneration failure and show that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion.