Luk Kelvin C, Covell Dustin J, Kehm Victoria M, Zhang Bin, Song Insung Y, Byrne Matthew D, Pitkin Rose M, Decker Samantha C, Trojanowski John Q, Lee Virginia M-Y
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283 USA.
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283 USA.
Cell Rep. 2016 Sep 20;16(12):3373-3387. doi: 10.1016/j.celrep.2016.08.053.
The accumulation and propagation of misfolded α-synuclein (α-Syn) is a central feature of Parkinson's disease and other synucleinopathies. Molecular compatibility between a fibrillar seed and its native protein state is a major determinant of amyloid self-replication. We show that cross-seeded aggregation of human (Hu) and mouse (Ms) α-Syn is bidirectionally restricted. Although fibrils formed by Hu-Ms-α-Syn chimeric mutants can overcome this inhibition in cell-free systems, sequence homology poorly predicts their efficiency in inducing α-Syn pathology in primary neurons or after intracerebral injection into wild-type mice. Chimeric α-Syn fibrils demonstrate enhanced or reduced pathogenicities compared with wild-type Hu- or Ms-α-Syn fibrils. Furthermore, α-Syn mutants induced to polymerize by fibrillar seeds inherit the functional properties of their template, suggesting that transferable pathogenic and non-pathogenic states likely influence the initial engagement between exogenous α-Syn seeds and endogenous neuronal α-Syn. Thus, transmission of synucleinopathies is regulated by biological processes in addition to molecular compatibility.
错误折叠的α-突触核蛋白（α-Syn）的积累和传播是帕金森病和其他突触核蛋白病的核心特征。纤维状种子与其天然蛋白质状态之间的分子兼容性是淀粉样蛋白自我复制的主要决定因素。我们发现人（Hu）和小鼠（Ms）α-Syn的交叉种子聚集受到双向限制。尽管由Hu-Ms-α-Syn嵌合突变体形成的纤维可以在无细胞系统中克服这种抑制作用，但序列同源性很难预测它们在原代神经元中或脑内注射到野生型小鼠后诱导α-Syn病理的效率。与野生型Hu-或Ms-α-Syn纤维相比，嵌合α-Syn纤维表现出增强或降低的致病性。此外，由纤维状种子诱导聚合的α-Syn突变体继承了其模板的功能特性，这表明可转移的致病和非致病状态可能影响外源性α-Syn种子与内源性神经元α-Syn之间的初始结合。因此，除了分子兼容性外，突触核蛋白病的传播还受生物学过程的调节。
