Hyperphosphorylation Renders Tau Prone to Aggregate and to Cause Cell Death.
Hyperphosphorylation Renders Tau Prone to Aggregate and to Cause Cell Death.
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DOI：
10.1007/s12035-020-02034-w
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发表时间：
2020-11
影响因子：
5.1
通讯作者：
Kuo MH
中科院分区：
文献类型：
--
作者：
Liu M;Sui D;Dexheimer T;Hovde S;Deng X;Wang KW;Lin HL;Chien HT;Kweon HK;Kuo NS;Ayoub CA;Jimenez-Harrison D;Andrews PC;Kwok R;Bochar DA;Kuret J;Fortin J;Tsay YG;Kuo MH
阿尔茨海默病（AD）是一种神经退行性疾病，迄今没有治愈或预防方法。过度磷酸化的tau形成与认知障碍进展密切相关的神经原纤维缠结（nft）。动物研究证实了过度磷酸化的tau蛋白的致病作用。了解异常磷酸化如何使正常的tau蛋白容易形成有毒的原纤维是描述分子病理学和开发有效的阿尔茨海默病药物的关键。产生具有疾病相关的超磷酸化和分子特征的tau是关键步骤。在这里，我们报道了与疾病密切相关的重组过磷酸化tau蛋白（p-tau）的制备和表征。由PIMAX方法产生的P-tau导致与AD神经病理进展相关的多个表位磷酸化。与需要聚集诱导剂且对细胞功能影响最小的未修饰tau形成鲜明对比的是，p-tau形成无诱导剂的原纤维，引发线粒体超氧化物峰值，诱导细胞凋亡，并在亚微摩尔浓度下导致细胞死亡。活性氧抑制剂可抑制p -tau诱导的细胞凋亡。过度磷酸化明显引起疾病相关构象的快速形成。在聚集和细胞毒性方面，p-tau都表现出播种活性，将未修饰的tau转化为细胞毒性物质，并增加了成纤维化的倾向。p-tau的这些特征与新出现的观点一致，即过度磷酸化导致tau成为易于聚集和细胞毒性的物种，这是AD和其他tau病弥漫性病理的基础。我们的结果进一步表明，p-tau为阿尔茨海默病的机制和药物发现研究提供了一个可行的工具。
Alzheimer’s disease (AD) is a neurodegenerative disorder without a cure or prevention to date. Hyperphosphorylated tau forms the neurofibrillary tangles (NFTs) that correlate well with the progression of cognitive impairments. Animal studies demonstrated the pathogenic role of hyperphosphorylated tau. Understanding how abnormal phosphorylation renders a normal tau prone to form toxic fibrils is key to delineating molecular pathology and to developing efficacious drugs for AD. Production of a tau bearing the disease-relevant hyperphosphorylation and molecular characters is a pivotal step. Here we report the preparation and characterization of a recombinant hyperphosphorylated tau (p-tau) with strong relevance to disease. P-tau generated by the PIMAX approach resulted in phosphorylation at multiple epitopes linked to the progression of AD neuropathology. In stark contrast to unmodified tau that required an aggregation inducer, and which had minimal effects on cell functions, p-tau formed inducer-free fibrils that triggered a spike of mitochondrial superoxide, induced apoptosis, and caused cell death at sub-micromolar concentrations. P-tau-induced apoptosis was suppressed by inhibitors for reactive oxygen species. Hyperphosphorylation apparently caused rapid formation of a disease-related conformation. In both aggregation and cytotoxicity, p-tau exhibited seeding activities that converted the unmodified tau into a cytotoxic species with increased propensity for fibrillization. These characters of p-tau are consistent with the emerging view that hyperphosphorylation causes tau to become an aggregation-prone and cytotoxic species that underlies diffusible pathology in AD and other tauopathies. Our results further suggest that p-tau affords a feasible tool for Alzheimer’s disease mechanistic and drug discovery studies.
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DOI：
10.1074/jbc.m114.589309
发表时间：
2015-01-09
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Falcon B;Cavallini A;Angers R;Glover S;Murray TK;Barnham L;Jackson S;O'Neill MJ;Isaacs AM;Hutton ML;Szekeres PG;Goedert M;Bose S
通讯作者：
Bose S
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
影响因子：
82.9
作者：
Alonso, AD;GrundkeIqbal, I;Iqbal, K
通讯作者：
Iqbal, K
DOI：
10.1073/pnas.121119298
发表时间：
2001-06-05
影响因子：
11.1
作者：
Alonso, AD;Zaidi, T;Iqbal, K
通讯作者：
Iqbal, K
DOI：
10.1073/pnas.96.11.6020
发表时间：
1999-05-25
影响因子：
11.1
作者：
Fancy, DA;Kodadek, T
通讯作者：
Kodadek, T