泛素化修饰与身体调控及疾病的关系(3),细胞生物学论文

　　神经退行性疾病如帕金森或阿尔兹海默氏病又或者多聚谷氨酰胺重复疾病如亨廷顿氏病都以蛋白质聚集体的毒性累积为特征，从而破坏细胞稳态与神经元功能而致病。而尽管不同疾病中蛋白质聚集体的组分与定位都不尽相同，它们都对抗泛素抗体有免疫活性，并且越来越多的研究证明，泛素依赖的蛋白酶体降解系统（Ub-proteasome system, UPS）的异常与蛋白质聚集体的形成紧密相关从而参与神经退行性病变[64,65].
　　
　　（1）泛素化修饰与帕金森氏病。帕金森氏病（Parkinson's disease）以进行性的黑质多巴胺神经元丧失为特征，从而导致肌肉颤抖，震颤与运动迟缓。路易氏小体（Lewy bodies），主要由a-突触核蛋白（a-synuclein）组成的蛋白质聚集体，正是帕金森氏病的诊断特征，而大多数的路易氏小体中的a-突触核蛋白都处于单泛素化或双泛素化修饰的状态下[ 6 6 ].在培养的多巴胺能细胞中，泛素化似乎能增加蛋白质聚集程度与a-突触核蛋白的神经毒性[67].但是有趣的是，泛素化的效果具有位点特异性，不同赖氨酸位点的泛素化可以显着增强或者抑制原纤维的形成[68].
　　
　　（2）泛素化修饰与阿尔兹海默氏病。阿尔兹海默氏病（Alzheimer's disease）是老年人中最常见的神经退行性疾病，患有此病的病人会出现进展性的记忆丧失与认知障碍，并最终发展为痴呆。神经元胞外的b-淀粉样蛋白斑和胞内的神经原纤维缠结是阿尔兹海默氏病病人的病理特征之一，而二者正是由高度磷酸化与泛素化的tau蛋白组成的蛋白质聚集体。从阿尔兹海默氏病病人的脑组织标本与tau蛋白病变的小鼠模型的研究中发现， UPS效率的降低以及受到抑制的自噬-溶酶体通路与tau在突触末端的异常累积明显正相关[69,70].
　　
　　3结论与展望
　　
　　尽管许多泛素化修饰的原则得到了阐明，但泛素化修饰的生化机制与生理功能远未得到充分理解，例如，泛素化本身如何被调控以及泛素化与其他PTM如磷酸化、乙酰化之间的相互关系。本文简要介绍了泛素化的一些细胞生物学功能和泛素化异常参与的两种重要疾病-癌症与神经退行性疾病，尽管由于篇幅所限，许多泛素化参与的生物学过程与疾病未能详细阐述，但本文对了解泛素化的功能与意义的基本轮廓有所裨益。
　　
　　未来的研究会进一步聚焦于泛素化修饰作为一个动态网络，如何参与生理学进程又怎样影响生物学功能。例如，不同的E2s与E3s之间的联系，不同的泛素化修饰种类（单泛素化、多泛素化以及多聚泛素化）以及不同的多聚泛素化链（连接通过Met1,Lys6, Lys11, Lys27, Lys29, Lys33, Lys48和Lys63）仍需进一步研究[71].与此同时，对于泛素化修饰的进一步理解也必将推动一系列相关疾病的研究与治疗，近期，线性泛素化通路（linear ubiquitination pathway）与炎症、肿瘤与自身免疫性疾病的相互关系取得了巨大突破，并有望为上述疾病的治疗提供新思路[72].因此，随着对泛素化修饰的深入研究与治疗技术的不断发展，对泛素化通路进行操作将成为一种富有前景的高度特异性的治疗方法。
　　
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