Department of Neurology and the UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
UNC Proteomics Core Facility, Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
Cell Rep. 2021 Apr 27;35(4):109037. doi: 10.1016/j.celrep.2021.109037.
The prion-like spread of tau pathology could underlie a spectrum of clinical syndromes including Alzheimer's disease (AD). Although evidence indicates that tau is transmissible, it is unclear how pathogenic tau seeds are processed in neurons. Here, we analyze fibrillar wild-type and disease-associated P301L tau seeds by using in vitro and neuronal assays. We show that P301L seeds are uniquely modified by post-translational modifications (PTMs) within the microtubule-binding region (MTBR). Although these modifications do not alter tau seed trafficking or localization, acetylated tau variants show accelerated tau aggregation, enhanced tau PTM priming, and prion-like templating. To explain the enhanced tau seed acetylation, we demonstrate that P301L seeds undergo auto-acetylation. Moreover, tau acts generally to inhibit HDAC6 deacetylase activity by preventing HDAC6 phosphorylation, leading to increased substrate acetylation. Our study highlights complex post-translational regulation of transmissible tau seeds and provides insight into the biological properties of tau strains in AD and other tauopathies.
tau 病理的类朊病毒传播可能是包括阿尔茨海默病（AD）在内的一系列临床综合征的基础。尽管有证据表明 tau 是可传播的，但尚不清楚致病性 tau 种子在神经元中是如何被加工的。在这里，我们通过体外和神经元测定分析了纤维状野生型和与疾病相关的 P301L tau 种子。我们表明，P301L 种子在微管结合区（MTBR）内被独特的翻译后修饰（PTMs）修饰。尽管这些修饰不会改变 tau 种子的运输或定位，但乙酰化 tau 变体显示出加速的 tau 聚集、增强的 tau PTM 引发和类朊病毒模板。为了解释增强的 tau 种子乙酰化，我们证明 P301L 种子发生自身乙酰化。此外，tau 通过防止 HDAC6 磷酸化通常起抑制 HDAC6 脱乙酰酶活性的作用，导致底物乙酰化增加。我们的研究强调了可传播 tau 种子的复杂翻译后调节，并深入了解 AD 和其他 tau 病中 tau 菌株的生物学特性。
