Aggregation prone molecules, such as tau, form both historically well characterized fibrillar deposits (neurofibrillary tangles) and recently identified phosphate-buffered saline (PBS) extract species called proteopathic seeds. Both can cause normal endogenous tau to undergo templated misfolding. The relationship of these seeds to the fibrils that define tau-related diseases is unknown. We characterized the aqueous extractable and sarkosyl insoluble fibrillar tau species derived from human Alzheimer brain using mass spectrometry and in vitro bioassays. Post-translational modifications (PTMs) including phosphorylation, acetylation and ubiquitination are identified in both preparations. PBS extract seed competent tau can be distinguished from sarkosyl insoluble tau by the presence of overlapping, but less abundant, PTMs and an absence of some PTMs unique to the latter. The presence of ubiquitin and other PTMs on the PBS-extracted tau species correlates with the amount of tau in the seed competent size exclusion fractions, with the bioactivity and with the aggressiveness of clinical disease. These results demonstrate that the PTMs present on bioactive, seed competent PBS extract tau species are closely related to, but distinct from, the PTMs of mature paired helical filaments, consistent with the idea that they are a forme fruste of tau species that ultimately form fibrils.

中文翻译：

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阿尔茨海默病蛋白病 tau 种子在生物化学上是成熟配对螺旋丝的形式

易于聚集的分子，例如 tau，形成历史上明确表征的纤维沉积物（神经原纤维缠结）和最近发现的磷酸盐缓冲盐水 (PBS) 提取物，称为蛋白质种子。两者都会导致正常的内源性 tau 蛋白发生模板化错误折叠。这些种子与定义 tau 相关疾病的原纤维的关系尚不清楚。我们使用质谱和体外生物测定法对源自人类阿尔茨海默病大脑的水可提取和肌氨酰不溶性纤维状 tau 蛋白进行了表征。在两种制剂中均鉴定出翻译后修饰 (PTM)，包括磷酸化、乙酰化和泛素化。PBS 提取物种子感受态 tau 蛋白与肌氨酰不溶性 tau 蛋白可通过存在重叠但丰度较低的 PTM 以及不存在后者特有的某些 PTM 来区分。PBS 提取的 tau 物种上泛素和其他 PTM 的存在与种子感受态尺寸排阻级分中 tau 的含量、生物活性以及临床疾病的侵袭性相关。这些结果表明，具有生物活性、种子活性的 PBS 提取物 tau 物种上存在的 PTM 与成熟的成对螺旋丝的 PTM 密切相关，但又不同，这与它们是最终形成原纤维的 tau 物种的形态截头的观点一致。 。