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首页> 外文期刊>The European Journal of Neuroscience >Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration.
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Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration.

机译：涉及阿尔茨海默氏神经原纤维变性的激酶，磷酸酶和tau位点。

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Microtubule associated protein (MAP) tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) and related tauopathies; in this form it is the major protein subunit of paired helical filaments (PHF)eurofibrillary tangles. However, the nature of protein kinases and phosphatases and tau sites involved in this lesion has been elusive. We investigated self-assembly and microtubule assembly promoting activities of hyperphosphorylated tau isolated from Alzheimer disease brain cytosol, the AD abnormally hyperphosphorylated tau (AD P-tau) before and after dephosphorylation by phosphoseryl/phosphothreonyl protein phosphatase-2A (PP-2A), and then rephosphorylation by cyclic AMP-dependent protein kinase (PKA), calcium, calmodulin-dependent protein kinase II (CaMKII), glycogen synthase kinase-3beta (GSK-3beta) and cyclin-dependent protein kinase 5 (cdk5) in different kinase combinations. We found that (i) dephosphorylation of AD P-tau by PP-2A inhibits its polymerization into PHF/straight filaments (SF) and restores its binding and ability to promote assembly of tubulin into microtubules; (ii) rephosphorylation of PP-2A-dephosphorylated AD P-tau by sequential phosphorylation by PKA, CaMKII and GSK-3beta or cdk5, and as well as by cdk5 and GSK-3beta, promotes its self-assembly into tangles of PHF similar to those seen in Alzheimer brain, and (iii) phosphorylation of tau sites required for this pathology are Thr231 and Ser262, along with several sites flanking the microtubule binding repeat region. Phosphorylation of recombinant human brain tau(441) yielded similar results as the PP-2A dephosphorylated AD P-tau, except that mostly SF were formed. The conditions for the abnormal hyperphosphorylation of tau that promoted its self-assembly also induced the microtubule assembly inhibitory activity. These findings suggest that activation of PP-2A or inhibition of either both GSK-3beta and cdk5 or one of these two kinases plus PKA or CaMKII might be required to inhibit Alzheimer neurofibrillary degeneration.
机译：微管相关蛋白（MAP）tau在阿尔茨海默氏病（AD）和相关疾病中异常磷酸化。它是成对螺旋丝（PHF）/神经原纤维缠结的主要蛋白质亚基。然而，涉及该病灶的蛋白激酶，磷酸酶和tau位点的性质难以捉摸。我们调查了自组装和微管组装促进活性的磷酸化tau分离自Alzheimer病脑细胞溶胶，AD异常的过度磷酸化tau（AD P-tau）磷酸去磷酸化前后的磷酸丝氨酸/磷酸乙二醛蛋白磷酸酶2A（PP-2A）和然后通过环AMP依赖性蛋白激酶（PKA），钙，钙调蛋白依赖性蛋白激酶II（CaMKII），糖原合酶激酶-3beta（GSK-3beta）和细胞周期素依赖性蛋白激酶5（cdk5）进行不同磷酸化的重新磷酸化作用。我们发现：（i）PP-2A对AD P-tau的去磷酸化抑制了其聚合成PHF /直丝（SF），并恢复了其结合和促进微管蛋白组装成微管的能力; （ii）通过PKA，CaMKII和GSK-3beta或cdk5以及cdk5和GSK-3beta的顺序磷酸化PP-2A-去磷酸化的AD P-tau的再磷酸化，促进其自组装成类似于PHF的缠结（iii）这种病理所需的tau位点的磷酸化是Thr231和Ser262，以及位于微管结合重复区域两侧的几个位点。重组人脑tau（441）的磷酸化产生的结果与PP-2A去磷酸化的AD P-tau相似，但主要是形成了SF。促进tau自组装的tau异常过度磷酸化的条件也诱导了微管组装的抑制活性。这些发现表明，可能需要抑制PP-2A的激活或抑制GSK-3beta和cdk5或抑制这两种激酶之一，再加上PKA或CaMKII才能抑制阿尔茨海默氏症神经原纤维变性。

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