Neuron：可导致癫痫患者脑功能障碍的蛋白质

佚名

    日本研究人员日前发现，一种名为“Ａｒｃａｄｌｉｎ”的蛋白质可导致某些癫痫患者出现脑功能障碍。

    东京都神经科学综合研究所和大阪大学等机构的研究人员在８日的美国《神经元》杂志网络版上发表论文说，他们发现，一些重度癫痫患者如果反复出现强烈痉挛，他们脑神经细胞接合部位的突触数目会减少，从而引发记忆力衰退等脑功能障碍。研究人员在对大白鼠的实验中发现，当大白鼠痉挛发作时，它们脑神经细胞内的蛋白质“Ａｒｃａｄｌｉｎ”就会大量产生。进一步研究表明，这种蛋白质可使在脑神经突触间起黏结作用的神经细胞表面蛋白减少，造成脑神经突触间接合中断。

     研究人员认为，重度癫痫患者脑神经细胞内“Ａｒｃａｄｌｉｎ”大量产生，造成了脑神经突触间接合中断，进而导致大量突触消失，患者出现脑功能障碍。如果能找到一种物质，抑制可促使“Ａｒｃａｄｌｉｎ”大量生成的酶，就有可能避免上述情况。（新华网）

原始出处:

Neuron, Vol 56, 456-471, 08 November 2007

Article

Activity-Induced Protocadherin Arcadlin Regulates Dendritic Spine Number by Triggering N-Cadherin Endocytosis via TAO2β and p38 MAP Kinases

Shin Yasuda,1,6 Hidekazu Tanaka,2,6, Hiroko Sugiura,1,6 Ko Okamura,2 Taiki Sakaguchi,2 Uyen Tran,4 Takako Takemiya,1 Akira Mizoguchi,3 Yoshiki Yagita,5 Takeshi Sakurai,5 E.M. De Robertis,4 and Kanato Yamagata1,

1 Department of Neuropharmacology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan
2 Department of Pharmacology, Osaka University Medical School, Suita, Osaka 565-0871, Japan
3 Department of Anatomy, Mie University School of Medicine, Tsu, Mie 514-8507, Japan
4 Howard Hughes Medical Institute and Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA
5 Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10128, USA

Corresponding author
Hidekazu Tanaka
htanaka@pharma1.med.osaka-u.ac.jp

Corresponding author
Kanato Yamagata
kyamagat@tmin.ac.jp

Synaptic activity induces changes in the number of dendritic spines. Here, we report a pathway of regulated endocytosis triggered by arcadlin, a protocadherin induced by electroconvulsive and other excitatory stimuli in hippocampal neurons. The homophilic binding of extracellular arcadlin domains activates TAO2β, a splice variant of the thousand and one amino acid protein kinase 2, cloned here by virtue of its binding to the arcadlin intracellular domain. TAO2β is a MAPKKK that activates the MEK3 MAPKK, which phosphorylates the p38 MAPK. Activation of p38 feeds-back on TAO2β, phosphorylating a key serine required for triggering endocytosis of N-cadherin at the synapse. Arcadlin knockout increases the number of dendritic spines, and the phenotype is rescued by siRNA knockdown of N-cadherin. This pathway of regulated endocytosis of N-cadherin via protocadherin/TAO2β/MEK3/p38 provides a molecular mechanism for transducing neuronal activity into changes in synaptic morphologies.

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