Fibrils formed in vitro from α-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid
Fibrils formed in vitro from α-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid
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DOI：
10.1021/bi991447r
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发表时间：
2000-03-14
期刊：
影响因子：
2.9
通讯作者：
Lansbury, PT
中科院分区：
文献类型：
--
作者：
Conway, KA;Harper, JD;Lansbury, PT
编码α -突触核蛋白基因的两个错义突变与罕见的早发性帕金森病（PD）有关。这些形式的PD，以及常见的特发性形式，其特征是在大脑的受影响区域存在称为路易体的细胞质神经元沉积物。路易小体含有α -突触核蛋白，其形式类似于源自阿尔茨海默病（AD）淀粉样斑块的纤维a β。α -突触核蛋白（A53T）的一种突变形式在体外比野生型蛋白更快地成纤维，这表明体外成纤维和/或寡聚化的速度与PD的进展之间可能存在相关性，类似于体外a β成纤维与家族性AD之间的关系。在本文中，α -突触核蛋白在体外产生的原纤维，野生型和两种突变型，都显示出与淀粉样原纤维非常相似的特征，包括一个切口和主要不分枝的形态（通过原子力和电子显微镜证明），独特的染料结合特性（刚果红和硫黄素T），以及反平行的β片结构（傅里叶变换红外光谱和圆二色光谱）。-突触核蛋白原纤维相对抵抗蛋白水解，这是原纤维a β和与疾病相关的朊蛋白原纤维形式所共有的特性。这些数据表明，帕金森病与阿尔茨海默病一样，是一种脑淀粉样蛋白疾病，与阿尔茨海默病不同，其特征是细胞质淀粉样蛋白（路易体）。除了淀粉样原纤维外，还有一种小的寡聚物形式。α -突触核蛋白，可能类似于A β原纤维，在原纤维出现之前被观察到。这个物种或相关的物种，而不是原纤维本身，可能是神经元死亡的原因。
Two missense mutations in the gene encoding alpha-synuclein have been linked to rare, early-onset forms of Parkinson's disease (PD). These forms of PD, as well as the common idiopathic form, are characterized by the presence of cytoplasmic neuronal deposits, called Lewy bodies, in the affected region of the brain. Lewy bodies contain alpha-synuclein in a form that resembles fibrillar A beta derived from Alzheimer's disease (AD) amyloid plaques. One of the mutant forms of alpha-synuclein (A53T) fibrillizes more rapidly in vitro than does the wild-type protein, suggesting that a correlation may exist between the rate of in vitro fibrillization and/or oligomerization and the progression of PD, analogous to the relationship between A beta fibrillization in vitro and familial AD. In this paper, fibrils generated in vitro from alpha-synuclein, wild-type and both mutant forms, are shown to possess very similar features that are characteristic of amyloid fibrils, including a wound and predominantly unbranched morphology (demonstrated by atomic force and electron microscopies), distinctive dye-binding properties (Congo red and thioflavin T), and antiparallel beta-sheet structure (Fourier transform infrared spectroscopy and circular dichroism spectroscopy). alpha-Synuclein fibrils are relatively resistant to proteolysis, a property shared by fibrillar A beta and the disease-associated fibrillar form of the prion protein. These data suggest that PD, like AD, is a brain amyloid disease that, unlike AD, is characterized by cytoplasmic amyloid (Lewy bodies). In addition to amyloid fibrils, a small oligomeric form. of alpha-synuclein, which may be analogous to the A beta protofibril, was observed prior to the appearance of fibrils. This species or a related one, rather than the fibril itself, may be responsible for neuronal death.