Molecular pathophysiology of α-Synuclein : Molecular mechanisms of neurodegenerative diseases

在对阿尔茨海默病（AD）脑中SDS不溶性物质进行生物化学研究后，鉴定了两种未知肽，并将其命名为AD淀粉样蛋白（NAC）的非A β组分，并通过cDNA克隆鉴定了NAC的前体蛋白NACP（上田等人，1993）。NACP现在被称为人类α-突触核蛋白（aS）。由于在AD和帕金森病（PD）脑中，神经变性发生在aS高度表达的那些区域中，因此可能aS的量是变性的关键因素。在AD中，我们已经发现异常的突触末梢和营养不良的神经突中aS的表达改变。在PD和痴呆与路易体（LB），我们已经表明，主要丝状组分的LB是aS，以及与主要丝状组分的神经元和神经胶质细胞质包涵体的多系统萎缩（MSA）的情况下。为了了解AS的病理生理作用，我们使用AS柱和人脑蛋白进行亲和层析，并揭示微管蛋白是一种AS结合蛋白。AS诱导纯化的微管蛋白聚合成微管。这种活性与tau的活性一样高。突变形式的aS失去了这种潜力。现在我们可以看到aS和Tau之间惊人的相似之处：两者具有相同的生理功能和病理特征，使患病大脑中的异常结构被称为Synucleinopathies和Tau opathies。这篇论文（Alim et al. JAD 2004）于2004年在美国科学促进会（AAAS）的网站上作为“突发新闻”向公众发布。在α S转染的多巴胺能MES23.5细胞中，我们已经显示了酪氨酸羟化酶（TH）表达的抑制，表明α S在TH基因的调节中的作用。TH是多巴胺合成的限速酶。同样在MES23.5细胞中，我们已经表明，氧化应激诱导内源性aS的C-末端的核转位，这意味着aS在细胞核中的作用。

After biochemical investigations of SDS-insoluble materials from Alzheimer's disease (AD) brains, two unknown peptides were identified and named as non-Aβ component of AD amyloid (NAC), and the precursor protein of NAC, NACP was identified by cDNA cloning (Ueda et al. 1993). NACP is now known as human α-Synuclein (aS). Since in both AD and Parkinson's disease (PD) brains neurodegeneration occurs in those areas where aS is highly expressed, it is possible that the amount of aS is the key factor for the degeneration. In AD we have shown an altered expression of aS in abnormal synaptic terminals and dystrophic neurites. In PD and dementia with Lewy bodies (LBs), we have shown that the main filamentous component of LBs is aS, as well as with the case of main filamentous component of neuronal and glial cytoplasmic inclusions of multiple system atrophy (MSA). To understand the pathophysiological role of aS, we have performed affinity chromatography using aS column and human brain proteins and revealed tubulin to be an aS binding protein. aS induced polymerization of purified tubulin into microtubules. This activity was as high as that of tau. Mutant forms of aS lost this potential. Now we can see a striking resemblance between aS and tau : both have the same physiological function and pathological features, making abnormal structures in diseased brains known as Synucleinopathies and Tauopathies. This paper (Alim et al. JAD 2004) was press released for public as "Breaking News" from the Web site of the American Association of the Advancement of Science (AAAS) in 2004. In aS-transfected dopaminergic MES23.5 cells, we have shown the inhibition of tyrosine hydroxylase (TH) expression, suggesting a role of aS in the regulation of the TH gene. TH is a rate-limiting enzyme for the synthesis of dopamine. Also in MES23.5 cells, we have shown that oxidative stress induces nuclear translocation of the C-terminus of endogenous aS, implying a role of aS in the nucleus.