Metal-dependent generation of reactive oxygen species from amyloid proteins implicated in neurodegenerative disease
Metal-dependent generation of reactive oxygen species from amyloid proteins implicated in neurodegenerative disease
复制标题
DOI：
10.1042/bst0361293
复制
发表时间：
2008-12-01
影响因子：
3.9
通讯作者：
Tabner, Brian J.
中科院分区：
文献类型：
--
作者：
Allsop, David;Mayes, Jennifer;Tabner, Brian J.
使用基于ESR光谱和自旋捕获的方法，我们已经证明a（淀粉样β肽）（与阿尔茨海默病有关），α -突触核蛋白（与帕金森病有关），ABri（英国痴呆肽）（负责家族性英国痴呆），朊蛋白的某些有毒片段（与传染性海绵状脑病有关）和胰淀素肽（在2型糖尿病患者的胰腺中发现）都具有在体外产生H(2)O(2)的共同能力。许多对照（反向、混乱和无毒肽）缺乏这种特性。我们还注意到，在测试的各种蛋白质产生H(2)O(2)的能力与其对培养细胞的毒性作用之间存在正相关关系。在A β和ABri的情况下，我们已经表明，H(2)O(2)是在聚集的早期阶段以短爆发的形式产生的，与原原纤维或低聚物的存在有关，而不是与成熟原纤维有关。H(2)O(2)很容易通过芬顿化学转化为具有攻击性的羟基自由基，这种极具活性的自由基可能是导致上述所有疾病中大部分氧化损伤的原因。我们认为，涉及相关淀粉样蛋白和某些过渡金属离子的氧化还原活性复合物的形成可能在几种不同蛋白质错误折叠障碍的发病机制中发挥重要作用。
Using a method based on ESR spectroscopy and spin-trapping, we have shown that A (amyloid beta-peptide) (implicated in Alzheimer's disease), alpha-synuclein (implicated in Parkinson's disease), ABri (British dementia peptide) (responsible for familial British dementia), certain toxic fragments of the prion protein (implicated in the transmissible spongiform encephalopathies) and the amylin peptide (found in the pancreas in Type 2 diabetes mellitus) all have the common ability to generate H(2)O(2) in vitro. Numerous controls (reverse, scrambled and non-toxic peptides) lacked this property. we have also noted a positive correlation between the ability of the various proteins tested to generate H(2)O(2) and their toxic effects on cultured cells. in the case of A beta and ABri, we have shown that H(2)O(2) is generated as a short burst during the early stages of aggregation and is associated with the presence of protofibrils or oligomers, rather than mature fibrils. H(2)O(2) is readily converted into the aggressive hydroxyl radical by Fenton chemistry, and this extremely reactive radical could be responsible for much of the oxidative damage seen in all of the above disorders. We suggest that the formation of a redox-active complex involving the relevant amyloidogenic protein and certain transition-metal ions could play an important role in the pathogenesis of several different protein misfolding disorders.