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首页> 外文期刊>Nature >The Ptdlns(3,4)P_2 phosphatase INPP4A is a suppressor of excitotoxic neuronal death
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The Ptdlns(3,4)P_2 phosphatase INPP4A is a suppressor of excitotoxic neuronal death

机译：Ptdlns（3,4）P_2磷酸酶INPP4A是兴奋性毒性神经元死亡的抑制剂

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摘要

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. Recent studies have indicated an important role for phosphoinositide metabolism in the aetiology of diseases such as cancer, diabetes, myopathy and inflammation. 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)P_2 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 in motor 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-aspartate-type 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.
机译：磷脂酰肌醇的磷酸化衍生物（统称为磷酸肌醇）出现在细胞膜的细胞质小叶中，并调节诸如囊泡转运，细胞骨架重组和信号转导的活性。最近的研究表明，磷酸肌醇代谢在诸如癌症，糖尿病，肌病和炎症的疾病的病因学中具有重要作用。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被很好地表征，但对调节紧密相关分子磷脂酰肌醇-的磷酸酶的功能知之甚少。 3,4-双磷酸酯（PtdIns（3,4）P_2）。在这里我们显示肌醇多磷酸磷酸酶4A（INPP4A），PtdIns（3,4）P_2磷酸酶，是中枢神经系统中谷氨酸兴奋性毒性的抑制剂。小鼠Inpp4a基因的靶向破坏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起着重要作用。值得注意的是，Inpp4a〜（-/-）小鼠表现出严重的非自愿运动障碍。在体外，通过短发夹RNA沉默Inpp4a基因使培养的初级纹状体神经元易受N-甲基-D-天冬氨酸型谷氨酸受体（NMDARs）介导的细胞死亡的影响。从机理上讲，INPP4A位于突触后密度，并调节突触NMDAR定位和NMDAR介导的兴奋性突触后电流。因此，INPP4A保护神经元免受兴奋性细胞死亡，从而维持大脑的功能完整性。我们的研究表明，PtdIns（3,4）P_2，PtdIns（3,4,5）P_3和作用于它们的磷酸酶可以具有独特的调节作用，并提供对PtdIns（3,4）独特方面和生理意义的洞察力。 P_2代谢。据我们所知，INPP4A代表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代谢与神经退行性和不自主运动的调节之间的直接联系的发现可能有助于开发新的方法来治疗神经退行性疾病。

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  • 来源
    《Nature》 |2010年第7297期|p.497-501|共5页
  • 作者

    Junko Sasaki; Satoshi Kofuji; Reietsu Itoh; Toshihiko Momiyama; Kiyohiko Takayama; Haruka Murakami; Shinsuke Chida; Yuko Tsuya; Shunsuke Takasuga; Satoshi Eguchi; Ken Asanuma; Yasuo Horie; Kouichi Miura; Elizabeth Michele Davies; Christina Mitchell; Masakazu Yamazaki; Hirokazu Hirai; Tadaomi Takenawa; Akira Suzuki; Takehiko Sasaki;

  • 作者单位

    Department of Medical Biology, Akita University Graduate School of Medicine, Akita 010-8543, Japan Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan;

    Department of Medical Biology, Akita University Graduate School of Medicine, Akita 010-8543, Japan Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan;

    Department of Medical Biology, Akita University Graduate School of Medicine, Akita 010-8543, Japan Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan;

    Department of Pharmacology, Jikei University School of Medicine, Tokyo 105-8461, Japan;

    Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan Department of Neurophysiology, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan;

    Department of Medical Biology, Akita University Graduate School of Medicine, Akita 010-8543, Japan Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan;

    Department of Medical Biology, Akita University Graduate School of Medicine, Akita 010-8543, Japan Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan;

    Department of Medical Biology, Akita University Graduate School of Medicine, Akita 010-8543, Japan Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan;

    Department of Medical Biology, Akita University Graduate School of Medicine, Akita 010-8543, Japan Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan;

    Department of Medical Biology, Akita University Graduate School of Medicine, Akita 010-8543, Japan Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan;

    Department of Medical Biology, Akita University Graduate School of Medicine, Akita 010-8543, Japan Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan;

    Department of Gastroenterology and Neurology, Akita University Graduate School of Medicine, Akita 010-8543, Japan;

    Department of Gastroenterology and Neurology, Akita University Graduate School of Medicine, Akita 010-8543, Japan;

    Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia;

    Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia;

    Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan;

    Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan Department of Neurophysiology, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan;

    Division of Lipid Biochemistry, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan Global COE Program, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan;

    Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan Division of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;

    Department of Medical Biology, Akita University Graduate School of Medicine, Akita 010-8543, Japan Global COE Program, Gunma University and Akita University, Gunma 371-8511, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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