Halting of Caspase Activity Protects Tau from MC1-Conformational Change and Aggregation.
Halting of Caspase Activity Protects Tau from MC1-Conformational Change and Aggregation.
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DOI：
10.3233/jad-150960
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发表时间：
2016-10-18
期刊：
影响因子：
--
通讯作者：
Wolak J
中科院分区：
文献类型：
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作者：
Mead E;Kestoras D;Gibson Y;Hamilton L;Goodson R;Jones S;Eversden S;Davies P;O'Neill M;Hutton M;Szekeres P;Wolak J
细胞内神经元缠结（NFT）是阿尔茨海默病和其他tau蛋白病的标志，其中tau蛋白（一种微管相关蛋白）失去了稳定微管的能力。包括磷酸化和截短在内的几种翻译后修饰增加了tau聚集的倾向，从而形成NFT;然而，tau构象变化和聚集的潜在机制仍有待确定。半胱天冬酶激活和随后的tau蛋白水解裂解被认为是这种疾病相关的病理构象的潜在触发因素。这项工作的目的是调查之间的联系，半胱天冬酶激活和疾病相关的构象变化的神经母细胞瘤细胞为基础的模型的自发tau聚集。我们证明，胱天蛋白酶诱导启动tau蛋白水解裂解和生成的构象改变和聚集的tau识别的MC1构象抗体。最重要的是，这些事件被证明与半胱天冬酶抑制剂减弱。这意味着旨在抑制半胱天冬酶介导的tau切割的治疗剂可能证明在减缓切割和聚集方面是有益的，从而可能阻止tau病理和疾病进展。
Intracellular neurofibrillary tangles (NFTs) are the hallmark of Alzheimer’s disease and other tauopathies in which tau, a microtubule-associated protein, loses its ability to stabilize microtubules. Several post-translational modifications including phosphorylation and truncation increase tau’s propensity to aggregate thus forming NFTs; however, the mechanisms underlying tau conformational change and aggregation still remain to be defined. Caspase activation and subsequent proteolytic cleavage of tau is thought to be a potential trigger of this disease-related pathological conformation. The aim of this work was to investigate the link between caspase activation and a disease-related conformational change of tau in a neuroblastoma cell-based model of spontaneous tau aggregation. We demonstrated that caspase induction initiates proteolytic cleavage of tau and generation of conformationally altered and aggregated tau recognized by the MC1 conformational antibody. Most importantly, these events were shown to be attenuated with caspase inhibitors. This implies that therapeutics aimed at inhibiting caspase-mediated tau cleavage may prove beneficial in slowing cleavage and aggregation, thus potentially halting tau pathology and disease progression.