Prefibrillar amyloid aggregates could be generic toxins in higher organisms
Prefibrillar amyloid aggregates could be generic toxins in higher organisms
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DOI：
10.1523/jneurosci.4809-05.2006
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发表时间：
2006-08-02
影响因子：
5.3
通讯作者：
Stefani, Massimo
中科院分区：
文献类型：
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作者：
Baglioni, Serena;Casamenti, Fiorella;Stefani, Massimo
40多种人类疾病与组织中特定多肽或蛋白质的纤维沉积有关。淀粉样纤维或其前体对细胞具有高度毒性，表明它们在疾病发病机制中发挥关键作用。与任何疾病无关的蛋白质在体外能够形成寡聚体和淀粉样蛋白组合体，其结构和细胞毒性与疾病相关多肽的聚集体相当。在分离的细胞中，这种毒性已被证明是由于离子动态平衡和氧化应激引起的膜通透性增加所致。在这里，我们将原核HypF的Src同源3结构域和N-末端结构域的聚合体显微注射到大鼠大脑基底核的大细胞内，这两个结构域都与淀粉样病无关。这两种蛋白质的前纤维聚集体，而不是它们的成熟纤维或可溶单体，以类似于细胞培养中看到的剂量依赖的方式损害胆碱能神经元的活性。然而，与培养细胞的情况相反，在我们的实验条件下，组织中的细胞应激之后不会出现类似水平的细胞死亡，这一结果很可能反映出存在减少聚集毒性的保护机制。这些发现支持这样的假设，即神经退行性疾病主要是由聚集过程中早期错误折叠的物种引起的仿制细胞功能障碍造成的。
More than 40 human diseases are associated with fibrillar deposits of specific peptides or proteins in tissue. Amyloid fibrils, or their precursors, can be highly toxic to cells, suggesting their key role in disease pathogenesis. Proteins not associated with any disease are able to form oligomers and amyloid assemblies in vitro displaying structures and cytotoxicity comparable with those of aggregates of disease-related polypeptides. In isolated cells, such toxicity has been shown to result from increased membrane permeability with disruption of ion homeostasis and oxidative stress. Here we microinjected into the nucleus basalis magnocellularis of rat brains aggregates of an Src homology 3 domain and the N-terminal domain of the prokaryotic HypF, neither of which is associated with amyloid disease. Prefibrillar aggregates of both proteins, but not their mature fibrils or soluble monomers, impaired cholinergic neuron viability in a dose-dependent manner similar to that seen in cell cultures. Contrary to the situation with cultured cells, however, under our experimental conditions, cell stress in tissue is not followed by a comparable level of cell death, a result that is very likely to reflect the presence of protective mechanisms reducing aggregate toxicity. These findings support the hypothesis that neurodegenerative disorders result primarily from a generic cell dysfunction caused by early misfolded species in the aggregation process.