α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation.
α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation.
复制标题
α-突触核蛋白在生理上是一种旋转的四聚体，可抵抗聚集。
DOI：
10.1038/nature10324
复制
发表时间：
2011-08-14
期刊：
影响因子：
64.8
通讯作者：
Selkoe, Dennis J.
中科院分区：
文献类型：
--
作者：
Bartels, Tim;Choi, Joanna G.;Selkoe, Dennis J.
帕金森病（PD）是第二常见的神经退行性疾病。越来越多的证据表明，α-突触核蛋白 (αSyn) 的错误折叠形式在帕金森病的发病机制中发挥着致病作用。 αSyn 的神经元内聚集发生在路易体和路易神经突中，这是 PD 和称为突触核蛋白病的相关疾病的细胞病理学标志。 αSyn 长期以来被定义为~14 kDa 的“天然展开”单体，据信只有在与脂质囊泡结合后才能获得 α-螺旋二级结构。这一概念源于体外研究中重组细菌表达方案的广泛使用，以及细胞培养和组织研究中过度表达、样品加热和/或变性凝胶的广泛使用。相比之下，我们报告在非变性条件下从神经元和非神经元细胞系、脑组织和活人类细胞中分离和分析的内源性αSyn大部分以~58 kDa的折叠四聚体形式出现。多种方法，包括分析超速离心、扫描透射电子显微镜和体内细胞交联，证实了四聚体的存在。天然的、细胞来源的 αSyn 在没有添加脂质的情况下显示出 α-螺旋结构，并且比迄今为止研究的重组 αSyn 具有更大的脂质结合能力。重组表达的单体在体外很容易聚集成淀粉样蛋白样原纤维，而天然人四聚体很少或没有发生淀粉样蛋白样聚集。基于这些发现，我们提出，在PD和其他人类突触核蛋白病中，螺旋折叠四聚体的不稳定先于αSyn错误折叠和聚集，并且稳定生理四聚体的小分子可以降低αSyn致病性。
Parkinson disease (PD) is the second most common neurodegenerative disorder. Growing evidence suggests a causative role of misfolded forms of the protein, α-synuclein (αSyn), in the pathogenesis of PD. Intraneuronal aggregates of αSyn occur in Lewy bodies and Lewy neurites, the cytopathological hallmarks of PD and the related disorders called synucleinopathies. αSyn has long been defined as a “natively unfolded” monomer of ∼14 kDa that is believed to acquire α-helical secondary structure only upon binding to lipid vesicles. This concept derives from the widespread use of recombinant bacterial expression protocols for in vitro studies, and of overexpression, sample heating and/or denaturing gels for cell culture and tissue studies. In contrast, we report that endogenous αSyn isolated and analyzed under non-denaturing conditions from neuronal and non-neuronal cell lines, brain tissue and living human cells occurs in large part as a folded tetramer of ∼58 kDa. Multiple methods, including analytical ultracentrifugation, scanning transmission electron microscopy and in vivo cell crosslinking, confirmed the occurrence of the tetramer. Native, cell-derived αSyn showed α-helical structure without lipid addition and had much greater lipid binding capacity than the recombinant αSyn studied heretofore. Whereas recombinantly expressed monomers readily aggregated into amyloid-like fibrils in vitro, native human tetramers underwent little or no amyloid-like aggregation. Based on these findings, we propose that destabilization of the helically folded tetramer precedes αSyn misfolding and aggregation in PD and other human synucleinopathies and that small molecules which stabilize the physiological tetramer could reduce αSyn pathogenicity.
登录
查看更多内容
影响因子：
5.6
作者：
Osenkowski, Pamela;Li, Hua;Ye, Wenjuan;Li, Dongyang;Aeschbach, Lorene;Fraering, Patrick C.;Wolfe, Michael S.;Selkoe, Dennis J.;Li, Huilin
通讯作者：
Li, Huilin
影响因子：
2.9
作者：
CHEN, YH;YANG, JT;MARTINEZ, HM
通讯作者：
MARTINEZ, HM
影响因子：
4.8
作者：
Quintas, A;Saraiva, MJM;Brito, RMM
通讯作者：
Brito, RMM
DOI：
10.1073/pnas.0802437105
发表时间：
2008-08-05
影响因子：
11.1
作者：
Scherzer, Clemens R.;Grass, Jeffrey A.;Schlossmacher, Michael G.
通讯作者：
Schlossmacher, Michael G.
影响因子：
2.9
作者：
Weinreb, PH;Zhen, WG;Lansbury, PT
通讯作者：
Lansbury, PT