Halliday Glenda M, McCann Heather
Prince of Wales, Medical Research Institute, Randwick, NSW, Australia.
Exp Neurol. 2008 Jan;209(1):12-21. doi: 10.1016/j.expneurol.2007.07.006. Epub 2007 Jul 17.
This article reviews the current knowledge on alpha-synuclein and its cellular locations in studies using human brain tissue. Alterations in the conformation and distribution of alpha-synuclein are examined in Parkinson's disease and the relationship between clinical symptoms and pathology explored. alpha-Synuclein as a molecular chaperone has several isoforms and is known to have different environment-dependent conformations. Processing methods for studying human brain tissue significantly impact on the conformational type of alpha-synuclein analysed, and antibody species used for the in situ detection of alpha-synuclein give variable results depending on the epitope visualised. Human studies show that alpha-synuclein is not isolated to neurons, but is also found in glia, making the interpretation of studies using brain tissue homogenates less clearly related to neurons. These methodological issues impact significantly on our understanding of the form, location, and therefore function of alpha-synuclein in normal human brain tissue. There are less methodological issues regarding highly aggregated alpha-synuclein found in the major hallmark of Parkinson's disease, the Lewy body. However, it remains unclear whether these alpha-synuclein inclusions are harmful to host neurons or provide protection. Several correlations exist between the clinical symptoms of Parkinson's disease and the distribution of Lewy pathology, the strongest being the association between limbic and cortical Lewy bodies and well-formed visual hallucinations. Further correlation studies in prospectively-followed patients and, perhaps more importantly, controls are required in order to determine normal versus pathologic alpha-synuclein and how to detect such differences in clinical situations.
本文综述了在使用人脑组织的研究中关于α-突触核蛋白及其细胞定位的现有知识。研究了帕金森病中α-突触核蛋白的构象和分布变化，并探讨了临床症状与病理学之间的关系。α-突触核蛋白作为一种分子伴侣有多种异构体，已知具有不同的环境依赖性构象。研究人脑组织的处理方法对所分析的α-突触核蛋白的构象类型有显著影响，用于原位检测α-突触核蛋白的抗体种类根据所观察的表位会给出不同的结果。人体研究表明，α-突触核蛋白并非仅存在于神经元中，在神经胶质细胞中也有发现，这使得对使用脑组织匀浆的研究结果的解读与神经元的关系不那么清晰。这些方法学问题对我们理解α-突触核蛋白在正常人类脑组织中的形式、定位以及功能有重大影响。对于在帕金森病主要标志路易小体中发现的高度聚集的α-突触核蛋白，方法学问题较少。然而，这些α-突触核蛋白包涵体对宿主神经元是有害还是提供保护仍不清楚。帕金森病的临床症状与路易小体病理分布之间存在多种相关性，其中最强的是边缘和皮质路易小体与典型视幻觉之间的关联。为了确定正常与病理性α-突触核蛋白以及如何在临床情况下检测这种差异，需要对前瞻性随访的患者，也许更重要的是对对照组进行进一步的相关性研究。
