日本秋田大学一个研究小组13日发表报告说，他们在动物实验中发现了脑神经细胞死亡的部分机制。
秋田大学教授佐佐木雄彦领导的研究小组13日在英国《自然》杂志网络版上发表报告说，如果脑神经细胞内分解无用磷脂的酶无法发挥作用，神经细胞就会死亡，从而导致运动机能障碍。
在实验过程中，研究人员培育出了体内缺乏这种酶的小鼠，结果其脑神经细胞内的无用磷脂无法分解，堆积在细胞中，导致细胞死亡，最终引起了小鼠身体颤抖等运动障碍。
佐佐木雄彦指出，虽然此前已经知道这种酶的存在，但是它与脑神经细胞死亡的关系尚不为人所知。他们的研究表明，可以利用这种酶开发治疗阿尔茨海默氏症、肌萎缩性侧索硬化症的方法以及减轻脑中风后遗症的方法等。(生物谷Bioon.com)
生物谷推荐原文出处：
Nature (2010) doi:10.1038/nature09023
The PtdIns(3,4)P2 phosphatase INPP4A is a suppressor of excitotoxic neuronal death
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
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 transduction1, 2. Recent studies have indicated an important role for phosphoinositide metabolism in the aetiology of diseases such as cancer, diabetes, myopathy and inflammation3, 4, 5. Although the biological functions of the phosphatases that regulate phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) 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)P2). 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 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)P2, PtdIns(3,4,5)P3 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)P2 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)P2 metabolism and the regulation of neurodegeneration and involuntary movements may aid the development of new approaches for the treatment of neurodegenerative disorders.
