Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease
Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease
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DOI：
10.1038/3311
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发表时间：
1998-11-01
期刊：
影响因子：
82.9
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突变与早发性帕金森病(1-3)(PD)有关。α-突触核蛋白是路易体的一种成分，路易体是帕金森病脑内黑质多巴胺能神经元特有的纤维状胞浆内含物(4)。遗传学和病理学之间的这种联系表明，α-突触核蛋白突变可能通过加速路易小体的形成而促进帕金森病的发病。为了验证这一点，我们在没有其他路易小体相关分子的情况下，在体外研究了α-突触核蛋白的折叠和聚集。我们在这里证明了α-突触核蛋白的两种突变形式(A53T和A30P)与野生型α-突触核蛋白(5)(WT)一样，在稀溶液中是无序的。然而，在较高的浓度下，形成路易体样纤维和离散的球形组件；A53T最快。因此，突变诱导的α-突触核蛋白原纤维形成的加速可能与家族性帕金森病的早期发病有关。
Two mutations in the gene encoding alpha-synuclein have been linked to early-onset Parkinson's disease(1-3) (PD). alpha-Synuclein is a component of Lewy bodies, the fibrous cytoplasmic inclusions characteristic of nigral dopaminergic neurons in the PD brain(4). This connection between genetics and pathology suggests that the alpha-synuclein mutations may promote PD pathogenesis by accelerating Lewy body formation. To test this, we studied alpha-synuclein folding and aggregation in vitro, in the absence of other Lewy body-associated molecules. We demonstrate here that both mutant forms of alpha-synuclein (A53T and A30P) are, like wild-type alpha-synuclein(5) (WT), disordered in dilute solution. However, at higher concentrations, Lewy body-like fibrils and discrete spherical assemblies are formed; most rapidly by A53T. Thus, mutation-induced acceleration of alpha-synuclein fibril formation may contribute to the early onset of familial PD.