Formation of highly toxic soluble amyloid beta oligomers by the molecular chaperone prefoldin
Formation of highly toxic soluble amyloid beta oligomers by the molecular chaperone prefoldin
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DOI：
10.1111/j.1742-4658.2008.06727.x
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发表时间：
2008-12
期刊：
影响因子：
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通讯作者：
M. Sakono;T. Zako;H. Ueda;M. Yohda;M. Maeda
中科院分区：
文献类型：
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作者：
M. Sakono;T. Zako;H. Ueda;M. Yohda;M. Maeda
阿尔茨海默病(AD)是一种神经系统疾病，其特征是大脑中存在淀粉样蛋白(Aβ，Aβ)多肽纤维和寡聚体。有研究表明，可溶性Aβ寡聚体，而不是Aβ纤维，由于其较高的毒性而导致神经退行性变和痴呆。最近的研究表明，Aβ也是在细胞内产生的，随后可以在那里积累。观察到Aβ对胞质蛋白酶体的抑制，表明Aβ位于胞质内。到目前为止，虽然已经确定了几种参与形成可溶性Aβ寡聚体的蛋白质，但没有一种蛋白质被证明能在体外诱导在AD大脑中发现的高分子质量(>；50 kDa)寡聚体的形成。在这里，我们研究了水母形状的分子伴侣预折叠蛋白(Pfd)对Aβ(1-42)多肽聚集的影响。PFD被认为在古生物中的从头蛋白折叠以及真核生物胞浆中肌动蛋白、微管蛋白和可能的其他蛋白质的生物发生中发挥着普遍的作用。我们发现重组热球菌能产生大分子量(50-250 kDa)的可溶性A-β寡聚体，而不是A-β纤维。我们还证明了可溶性Aβ寡聚体比Aβ纤维具有更强的毒性，并能够诱导细胞凋亡。由于PfD与人PfD和人脑中发现的PfD同源蛋白具有很高的序列同源性，这些结果表明PfD可能参与了体内胞液中有毒的可溶性Aβ寡聚体的形成。
Alzheimer’s disease (AD) is a neurological disorder characterized by the presence of amyloid β (Aβ) peptide fibrils and oligomers in the brain. It has been suggested that soluble Aβ oligomers, rather than Aβ fibrils, contribute to neurodegeneration and dementia due to their higher level of toxicity. Recent studies have shown that Aβ is also generated intracellularly, where it can subsequently accumulate. The observed inhibition of cytosolic proteasome by Aβ suggests that Aβ is located within the cytosolic compartment. To date, although several proteins have been identified that are involved in the formation of soluble Aβ oligomers, none of these have been shown to induce in vitro formation of the high‐molecular‐mass (> 50 kDa) oligomers found in AD brains. Here, we examine the effects of the jellyfish‐shaped molecular chaperone prefoldin (PFD) on Aβ(1–42) peptide aggregation in vitro. PFD is thought to play a general role in de novo protein folding in archaea, and in the biogenesis of actin, tubulin and possibly other proteins in the cytosol of eukaryotes. We found that recombinant Pyrococcus PFD produced high‐molecular‐mass (50–250 kDa) soluble Aβ oligomers, as opposed to Aβ fibrils. We also demonstrated that the soluble Aβ oligomers were more toxic than Aβ fibrils, and were capable of inducing apoptosis. As Pyrococcus PFD shares high sequence identity to human PFD and the PFD‐homolog protein found in human brains, these results suggest that PFD may be involved in the formation of toxic soluble Aβ oligomers in the cytosolic compartment in vivo.