Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, BMS J484, Gainesville, FL, 32610, USA.
Department of Neuroscience, University of Florida, Gainesville, FL, 32610, USA.
Acta Neuropathol Commun. 2023 Oct 27;11(1):172. doi: 10.1186/s40478-023-01664-0.
Distinctive post-translational modifications (PTM) characterize tau inclusions found in tauopathy patients. Using detergent-insoluble tau isolated from Alzheimer's disease (AD-tau) or Progressive Supranuclear Palsy (PSP-tau) patients, we provide insights into whether phosphorylation of critical residues determine templated tau seeding. Our initial data with phosphorylation-ablating mutations (Ser/Thr → Ala) on select sites of P301L tau showed no changes in seeding efficacy by AD-tau or PSP-tau. Interestingly, when specific sites in the R1-R2 repeat domains (Ser262/Thr263/Ser289/Ser305) were mutated to phosphorylation-mimicking amino acid Glu, it substantially reduced the seeding efficiency of AD-tau, but not PSP-tau seeds. The resultant detergent-insoluble tau shows deficient phosphorylation on AT8, AT100, AT180 and PHF1 epitopes, indicating inter-domain cooperativity. We further identify Ser305 as a critical determinant of AD-tau-specific seeding, whereby the phospho-mimicking Ser305Glu tau abrogates seeding by AD-tau but not PSP-tau. This suggests that phosphorylation on Ser305 could be related to the formation of disease-specific tau strains. Our results highlight the existence of a phospho-PTM code in tau seeding and further demonstrate the distinctive nature of this code in 4R tauopathies.
在患有 tau 病的患者中发现的 tau 包含物具有独特的翻译后修饰 (PTM)。使用从阿尔茨海默病 (AD-tau) 或进行性核上性麻痹 (PSP-tau) 患者中分离出的去污剂不溶性 tau，我们深入了解了关键残基的磷酸化是否决定了模板 tau 播种。我们最初的数据显示，在 P301L tau 的选定位点上进行磷酸化消除突变 (Ser/Thr→Ala)，AD-tau 或 PSP-tau 的种子效率没有变化。有趣的是，当 R1-R2 重复结构域中的特定位点 (Ser262/Thr263/Ser289/Ser305) 突变为磷酸化模拟氨基酸 Glu 时，它会大大降低 AD-tau 的种子效率，但不会降低 PSP-tau 的种子效率。由此产生的去污剂不溶性 tau 在 AT8、AT100、AT180 和 PHF1 表位上显示出磷酸化不足，表明结构域间的合作。我们进一步确定 Ser305 是 AD-tau 特异性播种的关键决定因素，磷酸化模拟 Ser305Glu tau 可阻断 AD-tau 的播种，但不能阻断 PSP-tau 的播种。这表明 Ser305 的磷酸化可能与疾病特异性 tau 株的形成有关。我们的结果强调了 tau 播种中存在磷酸化 PTM 密码，进一步证明了该密码在 4R tau 病中的独特性质。
