α-Synuclein chaperone suppresses nucleation and amyloidogenesis of prion protein
α-Synuclein chaperone suppresses nucleation and amyloidogenesis of prion protein
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DOI：
10.1016/j.bbrc.2019.10.120
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发表时间：
2020-01-01
影响因子：
3.1
通讯作者：
Honda, Ryo
中科院分区：
文献类型：
--
作者：
Shirasaka, Maki;Kuwata, Kazuo;Honda, Ryo
蛋白质错误折叠疾病是一组以可溶性蛋白质结构转化为淀粉样聚集体为特征的破坏性疾病。通常，结构转换通过单个疾病相关蛋白质的错误折叠而发生，例如帕金森病中的α-突触核蛋白（α S），阿尔茨海默病中的淀粉样蛋白β和传染性海绵状脑病（TSE）中的朊病毒蛋白（PrP）。然而，越来越多的证据表明，异源淀粉样蛋白之间的交叉相互作用显着影响淀粉样蛋白的形成和疾病的病理。在这里，我们显示在单体状态下的α S可以抑制体外PrP的淀粉样蛋白生成。硫磺素-T测定和透射电子误复制显示，单体α S抑制淀粉样蛋白生成的成核步骤，而不抑制生长步骤。表面等离子体共振和共沉降测定既没有检测到α S和单体PrP之间的相互作用，也没有检测到纤维状PrP。这些结果表明，α S抑制淀粉样蛋白的PrP通过结合到一个短暂积累的中间体，如部分未折叠状态。此外，我们发现，寡聚α S，这是最近建议与PrP相互作用，也没有与PrP相互作用。总之，我们的研究揭示了α S对PrP淀粉样蛋白生成的伴侣样活性，表明α S可能参与TSE的病理学。(C)2019爱思唯尔公司All rights reserved.
Protein misfolding diseases are a group of devastating disorders characterized by structural conversion of a soluble protein into an amyloid-like aggregate. Typically, the structural conversion occurs by misfolding of a single disease-associated protein, such as alpha-synuclein (alpha S) in Parkinson's disease, amyloid-beta in Alzheimer's disease, and prion protein (PrP) in transmissible spongiform encephalopathies (TSEs). However, accumulating evidence has implicated that cross-interactions between heterologous amyloidogenic proteins dramatically impact on amyloidogenesis and disease pathology. Here we show alpha S in a monomeric state can suppress amyloidogenesis of PrP in vitro. Thioflavin-T assays and transmission electron miscopy revealed that monomeric alpha S inhibits the nucleation step of amyloidogenesis without inhibiting the growing step. Surface plasmon resonance and co-sedimentation assays neither detected interaction between alpha S and monomeric PrP nor fibrillar PrP. These results suggested that alpha S suppress amyloidogenesis of PrP by binding to a transiently accumulated intermediate, such as a partially unfolded state. Moreover, we found that oligomeric alpha S, which was recently suggested to interact with PrP, also did not interact with PrP. Taken together, our study revealed a chaperon-like activity of alpha S against PrP amyloidogenesis, suggesting a possible involvement of alpha S in the pathology of TSEs. (C) 2019 Elsevier Inc. All rights reserved.