The PtdIns(3,4)P2 phosphatase INPP4A is a suppressor of excitotoxic neuronal death
The PtdIns(3,4)P2 phosphatase INPP4A is a suppressor of excitotoxic neuronal death
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DOI：
10.1038/nature09023
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发表时间：
2010-05-27
期刊：
影响因子：
64.8
通讯作者：
Sasaki, Takehiko
中科院分区：
文献类型：
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作者：
Sasaki, Junko;Kofuji, Satoshi;Sasaki, Takehiko
磷脂酰肌醇的磷酸化衍生物统称为磷酸肌醇，存在于细胞膜的细胞质小叶中，调节囊泡运输、细胞骨架重组和信号转导等活动(1,2)。最近的研究表明，磷酸肌醇代谢在癌症、糖尿病、肌病和炎症等疾病的病因学中发挥着重要作用(3-5)。尽管调节磷脂酰肌醇-3,4,5-三磷酸 (PtdIns(3,4,5)P-3) 的磷酸酶的生物学功能已得到很好的表征，但对于调节密切相关的分子磷脂酰肌醇-3,4-二磷酸 (PtdIns(3,4)P-2) 的磷酸酶的功能知之甚少。在这里，我们证明肌醇多磷酸磷酸酶 4A (INPP4A) 是一种 PtdIns(3,4)P2 磷酸酶，是中枢神经系统中谷氨酸兴奋毒性的抑制剂。小鼠 Inpp4a 基因的靶向破坏会导致纹状体神经变性，纹状体是基底神经节的输入核，在运动和认知行为中发挥核心作用。值得注意的是，Inpp4a(-/-) 小鼠表现出严重的不自主运动障碍。在体外，通过短发夹 RNA 沉默 Inpp4a 基因使培养的原代纹状体神经元容易受到 N-甲基-D-天冬氨酸型谷氨酸受体 (NMDAR) 介导的细胞死亡的影响。从机制上讲，INPP4A 存在于突触后密度，调节突触 NMDAR 定位和 NMDAR 介导的兴奋性突触后电流。因此，INPP4A 可以保护神经元免于兴奋性毒性细胞死亡，从而维持大脑功能的完整性。我们的研究表明，PtdIns(3,4)P-2、PtdIns(3,4,5)P-3 以及作用于它们的磷酸酶可以具有不同的调节作用，并深入了解 PtdIns(3,4)P-2 代谢的独特方面和生理意义。据我们所知，INPP4A 是第一个在神经元中具有抑制兴奋性毒性细胞死亡功能的信号蛋白。 PtdIns(3,4)P-2 代谢与神经退行性疾病和不自主运动调节之间直接联系的发现可能有助于开发治疗神经退行性疾病的新方法。
Phosphorylated derivatives of phosphatidylinositol, collectively referred to as phosphoinositides, occur in the cytoplasmic leaflet of cellular membranes and regulate activities such as vesicle transport, cytoskeletal reorganization and signal transduction(1,2). Recent studies have indicated an important role for phosphoinositide metabolism in the aetiology of diseases such as cancer, diabetes, myopathy and inflammation(3-5). Although the biological functions of the phosphatases that regulate phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P-3)have been well characterized, little is known about the functions of the phosphatases regulating the closely related molecule phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P-2). Here we show that inositol polyphosphate phosphatase 4A (INPP4A), a PtdIns(3,4)P2 phosphatase, is a suppressor of glutamate excitotoxicity in the central nervous system. Targeted disruption of the Inpp4a gene in mice leads to neurodegeneration in the striatum, the input nucleus of the basal ganglia that has a central role inmotor and cognitive behaviours. Notably, Inpp4a(-/-) mice show severe involuntary movement disorders. In vitro, Inpp4a gene silencing via short hairpin RNA renders cultured primary striatal neurons vulnerable to cell death mediated by N-methyl-D-aspartatetype glutamate receptors (NMDARs). Mechanistically, INPP4A is found at the postsynaptic density and regulates synaptic NMDAR localization and NMDAR-mediated excitatory postsynaptic current. Thus, INPP4A protects neurons from excitotoxic cell death and thereby maintains the functional integrity of the brain. Our study demonstrates that PtdIns(3,4)P-2, PtdIns(3,4,5)P-3 and the phosphatases acting on them can have distinct regulatory roles, and provides insight into the unique aspects and physiological significance of PtdIns(3,4)P-2 metabolism. INPP4A represents, to our knowledge, the first signalling protein with a function in neurons to suppress excitotoxic cell death. The discovery of a direct link between PtdIns(3,4)P-2 metabolism and the regulation of neurodegeneration and involuntary movements may aid the development of new approaches for the treatment of neurodegenerative disorders.