CRMP2 Hyperphosphorylation is Characteristic of Alzheimer's Disease and not a Feature Common to Other Neurodegenerative Diseases
CRMP2 Hyperphosphorylation is Characteristic of Alzheimer's Disease and not a Feature Common to Other Neurodegenerative Diseases
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DOI：
10.3233/jad-2011-110617
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发表时间：
2011-01-01
影响因子：
4
通讯作者：
Cole, Adam R.
中科院分区：
文献类型：
--
作者：
Williamson, Ritchie;van Aalten, Lidy;Cole, Adam R.
溃缩蛋白反应介导蛋白2（CRMP 2）是一种丰富的脑富集蛋白，其调节神经突生长。它被Cdk 5和GSK 3磷酸化，这些修饰在阿尔茨海默病（AD）患者的大脑中异常高。在表达突变的A β PP和PSEN 1但不表达单独的A β PP或tau的AD小鼠模型中，CRMP 2的磷酸化增加也是明显的，其中在淀粉样蛋白斑块和神经元缠结出现之前可以检测到CRMP 2的磷酸化，这表明它是AD发病机制中的早期事件。在这里，我们通过显示CRMP 2在单独过表达突变PSEN 1的小鼠中或在用可溶性寡聚A β（42）肽处理的培养神经元中没有过度磷酸化来扩展这些观察结果。类似地，CRMP 2磷酸化在严重神经变性（PMSC-1敲除）的小鼠模型中或在经受神经毒性浓度的NMDA或星形孢菌素的培养的神经元中没有增加。最有趣的是，CRMP 2磷酸化在与MAPT或Pick小体突变相关的额颞叶变性患者的额叶皮质中没有增加。总之，这些观察结果与以下假设一致：CRMP 2的异常磷酸化是AD特异性的，并且发生在A β PP过度加工的下游，但是过量的A β（42）肽或神经毒性都不足以促进过度磷酸化。
Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that regulates neurite outgrowth. It is phosphorylated by Cdk5 and GSK3, and these modifications are abnormally high in the brains of Alzheimer's disease (AD) patients. Increased phosphorylation of CRMP2 is also apparent in mouse models of AD that express mutated A beta PP and PSEN1, but not A beta PP or tau alone, where it is detectable before the appearance of amyloid plaques and neurofibrillary tangles, suggesting it is an early event in AD pathogenesis. Here, we have extended these observations by showing that CRMP2 is not hyperphosphorylated in mice overexpressing mutated PSEN1 alone, or in cultured neurons treated with soluble, oligomeric A beta(42) peptide. Similarly, CRMP2 phosphorylation was not increased in a mouse model of severe neurodegeneration (PMSC-1 knockout) or in cultured neurons subjected to neurotoxic concentrations of NMDA or staurosporine. Most interestingly, CRMP2 phosphorylation was not increased in frontal cortex from patients with frontotemporal lobar degeneration associated with mutations in MAPT or with Pick bodies. Together, these observations are consistent with the hypothesis that abnormal phosphorylation of CRMP2 is specific to AD and occurs downstream of excessive processing of A beta PP, but that neither excessive A beta(42) peptide nor neurotoxicity alone are sufficient to promote hyperphosphorylation.