Amyloid toxicity is independent of polypeptide sequence, length and chirality
Amyloid toxicity is independent of polypeptide sequence, length and chirality
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DOI：
10.1016/j.jmb.2007.08.012
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发表时间：
2008-01-18
影响因子：
5.6
通讯作者：
Serrano, Luis
中科院分区：
文献类型：
--
作者：
Pastor, M. Teresa;Kuemmerer, Nico;Serrano, Luis
通过使用淀粉样蛋白序列模式，我们在几个相关的淀粉样蛋白中鉴定了推测的六个残基的淀粉样蛋白致病伸展。在与模式匹配的序列延伸的基础上合成的六肽已被证明在体外形成淀粉样纤维。与较大的病理性多肽如Aβ(1-42)一样，这些短的淀粉样多肽形成小聚集体的异质混合物，导致PC12细胞和原代海马神经元的细胞死亡。这些六肽的小聚集体的有毒混合物结合到细胞膜上，并可以进一步内化，就像对天然淀粉样蛋白也观察到的那样。在神经元中，从全长Aβ(1-42)淀粉样多肽或其淀粉样蛋白伸展Aβ(16-21)多肽获得的有毒聚集体优先定位于突触，导致潜在的肌动蛋白细胞骨架的重组。这一过程不涉及膜和有毒物种之间的立体特异性相互作用，因为D-序列和L序列一样具有毒性，表明这不是受体介导的。基于这些结果，我们在这里提出，无论多肽序列、长度和氨基酸手性如何，淀粉样前纤维聚集体都通过与特定四级结构相关的共同细胞死亡机制发挥其细胞毒作用。然而，这些物种的毒性程度似乎取决于细胞膜的组成。(C)2007爱思唯尔有限公司。保留所有权利。
By using an amyloid sequence pattern, here we have identified putative six-residue amyloidogenic stretches in several relevant amyloid proteins. Hexapeptides synthesized on the bases of the sequence stretches matching the pattern have been shown to form amyloid fibrils in vitro. As larger pathological peptides such as A beta(1-42) do, these short amyloid peptides form heterogeneous mixtures of small aggregates that induce cell death in PC12 cells and primary hippocampal neurons. Toxic mixtures of small aggregates from these hexapeptides bind to cell membranes and can be further internalized, as also observed for natural amyloid proteins. In neurons, toxic aggregates obtained from the full length A beta(1-42) amyloid peptide or their amyloid stretch A beta(16-21) peptide preferentially localize in synapses, leading to the re-organization of the underlying actin cytoskeleton. This process does not involve stereospecific interactions between membrane and toxic species as D-sequences are as toxic as L ones, suggesting that is not receptor mediated. Based on these results, we propose here that regardless of polypeptide sequence, length and amino acid chirality, amyloid prefibrillar aggregates exert their cytotoxic effect through a common cell death mechanism related to a particular quaternary structure. The degree of toxicity of these species seems to depend, however, on cell membrane composition. (c) 2007 Elsevier Ltd. All rights reserved.