MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, London, UK.
J Neurochem. 2008 Jun 1;105(6):2343-52. doi: 10.1111/j.1471-4159.2008.05321.x.
Tangles containing hyperphosphorylated aggregates of insoluble tau are a pathological hallmark of progressive supranuclear palsy (PSP). Several phosphorylation sites on tau in PSP have been identified using phospho-specific antibodies, but no sites have been determined by direct sequencing due to the difficulty in enriching insoluble tau from PSP brain. We describe a new method to enrich insoluble PSP-tau and report eight phosphorylation sites [Ser46, Thr181, Ser202, Thr217, Thr231, Ser235, Ser396/Ser400 (one site) and Thr403/Ser404 (one site)] identified by mass spectrometry. We also describe a 35 kDa C-terminal tau fragment (tau35), lacking the N-terminus of tau but containing four microtubule-binding repeats (4R), that is present only in neurodegenerative disorders in which 4R tau is over-represented. Tau35 was readily detectable in PSP, corticobasal degeneration and 4R forms of fronto-temporal dementia with parkinsonism linked to chromosome 17, but was absent from control, Alzheimer's disease and Pick's disease brain. Our findings suggest the aggregatory characteristics of PSP-tau differ from those of insoluble tau in Alzheimer's disease brain and this might be related to the presence of a C-terminal cleavage product of tau.
含有不溶性 tau 异常磷酸化聚集物的缠结是进行性核上性麻痹（PSP）的病理学标志。已经使用磷酸化特异性抗体在 PSP 中的 tau 上鉴定了几个磷酸化位点，但由于难以从 PSP 大脑中富集不溶性 tau，因此尚未通过直接测序确定任何位点。我们描述了一种从 PSP 中富集不溶性 tau 的新方法，并通过质谱法报告了 8 个磷酸化位点[Ser46、Thr181、Ser202、Thr217、Thr231、Ser235、Ser396/Ser400（一个位点）和 Thr403/Ser404（一个位点）]。我们还描述了一个 35 kDa 的 C 端 tau 片段（tau35），它缺乏 tau 的 N 端，但含有四个微管结合重复（4R），仅存在于 4R tau 过度表达的神经退行性疾病中。tau35 在 PSP、皮质基底变性和与染色体 17 相关的额颞叶痴呆的 4R 形式中很容易检测到，但在对照、阿尔茨海默病和匹克病大脑中不存在。我们的发现表明 PSP-tau 的聚集特性与阿尔茨海默病大脑中不溶性 tau 的聚集特性不同，这可能与 tau 的 C 端裂解产物的存在有关。
