Prefibrillar amyloid protein aggregates share common features of cytotoxicity
Prefibrillar amyloid protein aggregates share common features of cytotoxicity
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DOI：
10.1074/jbc.m400348200
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发表时间：
2004-07-23
影响因子：
4.8
通讯作者：
Stefani, M
中科院分区：
文献类型：
--
作者：
Bucciantini, M;Calloni, G;Stefani, M
利用一系列荧光探针在体外和体内对暴露于HypF N -末端结构域的纤维前聚集体的小鼠成纤维细胞内游离Ca2 +浓度和氧化还原状态进行了研究。聚集体进入细胞质后，活性氧物质和游离Ca2 +水平早期升高，并最终导致细胞死亡。这种变化与细胞的活力直接相关，并且当细胞在还原剂存在下或在无Ca2 +培养基中培养时未观察到这种变化。此外，发现暴露于聚集体后的适度细胞应激是完全可逆的。结果表明，HypF - N（一种与临床疾病无关的蛋白质）的纤维前聚集体的细胞毒性与特定淀粉样变性相关蛋白质的类似类型聚集体所产生的毒性具有相同的根本来源。这些发现表明，错误折叠的蛋白质聚集体由于正常折叠蛋白质中被掩埋的结构区域（如疏水残基和多肽主链）暴露而刺激一般性细胞反应。它们也支持这样一种观点，即比以前所知更多的退行性病变可能被视为蛋白质沉积疾病。
The intracellular free Ca2+ concentration and redox status of murine fibroblasts exposed to prefibrillar aggregates of the HypF N-terminal domain have been investigated in vitro and in vivo using a range of fluorescent probes. Aggregate entrance into the cytoplasm is followed by an early rise of reactive oxygen species and free Ca2+ levels and eventually by cell death. Such changes correlate directly with the viability of the cells and are not observed when cell are cultured in the presence of reducing agents or in Ca2+-free media. In addition, moderate cell stress following exposure to the aggregates was found to be fully reversible. The results show that the cytotoxicity of prefibrillar aggregates of HypF-N, a protein not associated with clinical disease, has the same fundamental origin as that produced by similar types of aggregates of proteins linked with specific amyloidoses. These findings suggest that misfolded proteinaceous aggregates stimulate generic cellular responses as a result of the exposure of regions of the structure ( such as hydrophobic residues and the polypeptide main chain) that are buried in the normally folded proteins. They also support the idea that a higher number of degenerative pathologies than previously known might be considered as protein deposition diseases.