Duda J E, Lee V M, Trojanowski J Q
Center For Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
J Neurosci Res. 2000 Jul 15;61(2):121-7. doi: 10.1002/1097-4547(20000715)61:2<121::AID-JNR1>3.0.CO;2-4.
Beginning with the isolation of the fragment of alpha-synuclein (alpha-syn) known as the non-Abeta component of amyloid plaques (NAC peptide) from Alzheimer's disease (AD) brains, alpha-syn has been increasingly implicated in the pathogenesis of neurodegenerative diseases, which now are classified as synucleinopathies. Indeed, unequivocal evidence linking abnormal alpha-syn to mechanisms of brain degeneration came from discoveries of missense mutations in the alpha-syn gene pathogenic for familial Parkinson's disease (PD) in rare kindreds. Shortly thereafter, alpha-syn was shown to be a major component of Lewy bodies (LBs) and Lewy neurites in sporadic PD, dementia with LBs (DLB) and the LB variant of AD. Also, studies of brains from patients with AD caused by genetic abnormalities demonstrated many alpha-syn positive LBs. Further, alpha-syn was implicated in the formation of the glial (GCIs) and neuronal cytoplasmic inclusions of multiple system atrophy, and the LBs, GCIs and neuraxonal spheroids of neurodegeneration with brain iron accumulation type 1. Recently, two other members of the synuclein family, beta- and gamma-synuclein, have also been recognized to play a role in the pathogenesis of novel axonal lesions in PD and DLB. Evidence for a role of alpha-syn in the formation of filamentous aggregates was reinforced by in vitro studies showing aggregation and fibrillogenesis of mutant and wild type alpha-syn. Indeed, since the aggregation of brain proteins into presumptively toxic lesions is emerging as a common but poorly understood mechanistic theme in sporadic and hereditary neurodegenerative diseases, clarification of the mechanism of synuclein aggregation could augment efforts to develop novel and more effective therapies for many neurodegenerative disorders.
从阿尔茨海默病（AD）患者大脑中分离出被称为淀粉样斑块非Aβ成分（NAC肽）的α-突触核蛋白（α-syn）片段开始，α-syn越来越多地被认为与神经退行性疾病的发病机制有关，这些疾病现在被归类为突触核蛋白病。事实上，将异常α-syn与脑变性机制联系起来的确凿证据来自于在罕见家族中发现的对家族性帕金森病（PD）致病的α-syn基因错义突变。此后不久，α-syn被证明是散发性PD、路易体痴呆（DLB）和AD的路易体变异型中路易体（LBs）和路易神经突的主要成分。此外，对由基因异常引起的AD患者大脑的研究显示出许多α-syn阳性的LBs。此外，α-syn还与多系统萎缩的胶质细胞包涵体（GCIs）和神经元胞质包涵体的形成有关，以及与脑铁沉积1型神经退行性变的LBs、GCIs和神经轴突球状体有关。最近，突触核蛋白家族的另外两个成员β-和γ-突触核蛋白，也被认为在PD和DLB新型轴突病变的发病机制中起作用。体外研究表明突变型和野生型α-syn会聚集并形成纤维，这进一步证实了α-syn在丝状聚集体形成中的作用。事实上，由于脑蛋白聚集形成假定有毒性的病变正成为散发性和遗传性神经退行性疾病中一个常见但了解甚少的机制主题，阐明突触核蛋白聚集的机制可能会加大开发针对许多神经退行性疾病的新型更有效疗法的力度。
