日本研究人員日前發(fā)現(xiàn)，一種名為“Ａｒｃａｄｌｉｎ”的蛋白質(zhì)可導(dǎo)致某些癲癇患者出現(xiàn)腦功能障礙,。
東京都神經(jīng)科學(xué)綜合研究所和大阪大學(xué)等機(jī)構(gòu)的研究人員在８日的美國《神經(jīng)元》雜志網(wǎng)絡(luò)版上發(fā)表論文說,，他們發(fā)現(xiàn)，一些重度癲癇患者如果反復(fù)出現(xiàn)強(qiáng)烈痙攣,，他們腦神經(jīng)細(xì)胞接合部位的突觸數(shù)目會減少,，從而引發(fā)記憶力衰退等腦功能障礙。研究人員在對大白鼠的實驗中發(fā)現(xiàn),，當(dāng)大白鼠痙攣發(fā)作時,，它們腦神經(jīng)細(xì)胞內(nèi)的蛋白質(zhì)“Ａｒｃａｄｌｉｎ”就會大量產(chǎn)生,。進(jìn)一步研究表明，這種蛋白質(zhì)可使在腦神經(jīng)突觸間起黏結(jié)作用的神經(jīng)細(xì)胞表面蛋白減少,，造成腦神經(jīng)突觸間接合中斷,。
研究人員認(rèn)為，重度癲癇患者腦神經(jīng)細(xì)胞內(nèi)“Ａｒｃａｄｌｉｎ”大量產(chǎn)生,，造成了腦神經(jīng)突觸間接合中斷,，進(jìn)而導(dǎo)致大量突觸消失，患者出現(xiàn)腦功能障礙,。如果能找到一種物質(zhì),，抑制可促使“Ａｒｃａｄｌｉｎ”大量生成的酶，就有可能避免上述情況,。（新華網(wǎng)）
原始出處:
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
[email protected]
Corresponding author
Kanato Yamagata
[email protected]
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.
