Mechanistic insights into the link between the A152T risk variant and tauopathy

Tau基因(MAPT)的致病突变与tau病的发生有关，但A152T突变是一种独特的风险因素，可作为一系列疾病的危险因素，包括阿尔茨海默病(AD)、进行性核上性瘫痪(PSP)、皮质基底膜变性(CBD)和路易体痴呆(DLB)。作为研究tau在神经退行性变中作用的非常规方法，我们认为，了解A152T变体如何调节AD和相关疾病的风险可以揭示常见的疾病机制(S)，揭示增加对tau毒性的弹性和改变患者疾病表型的新策略。鉴于一个新的潜在的磷表位的引入，我们质疑A152T变体是否可能通过改变T152或邻近的T153残基上的tau的磷酸化来影响疾病风险。产生了一系列新的抗体来测试这一想法，这些抗体显示，与非携带者相比，A152T携带者以及表达A152T-AAV的小鼠死后脑组织中T153(PT153)上过度磷酸化的可溶性tau物种显著积累。因此，本项目将调查A152T变体通过促进pT153阳性tau的积累和增加的溶解性来调节疾病风险的总体假设，pT153阳性tau随后启动tau下游病理磷酸化事件，并对tau介导的毒性至关重要。值得注意的是，T153和tau的其他丝氨酸/苏氨酸-脯氨酸基序上的磷酸化已被证明是tau毒性所必需的，尽管pT153对tau毒性的贡献仍未得到测试。在阐明A152T携带者和非携带者中pT153在脑内的沉积模式时， 拟议的研究将确定pT153阳性是否与神经退行性变一致。利用定点突变和体细胞脑转基因，我们将确定体内是否需要pT153来实现tau的毒性。最后，结合能够在单细胞水平获得全球基因表达谱的快速发展的技术，我们将评估A152T变体的表达是否对单个细胞群体的转录组产生差异影响。我们预计，在揭示A152T影响tau病风险的机制，并破译pT153参与tau毒性的过程中，当前的项目可以找到新的方法来阻断tau介导的AD和相关疾病的神经变性。

Pathogenic mutations in the tau gene (MAPT) are linked to the onset of tauopathy, but the A152T mutation is unique in acting as a risk factor for a range of disorders including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB). As an unconventional approach to investigate the role of tau in neurodegeneration, we reasoned that understanding how the A152T variant modulates risk of AD and related disorders could reveal a common disease mechanism(s), uncovering novel strategies to increase resilience to tau toxicity and modify disease phenotypes in patients. Given the introduction of a new potential phosphoepitope, we questioned whether the A152T variant might impact disease risk through altered phosphorylation of tau on either T152 or the neighboring T153 residue. A series of novel antibodies were generated to test this idea, which revealed significant accumulation of soluble tau species hyperphosphorylated on T153 (pT153) in postmortem brain tissue from A152T carriers compared to noncarriers, as well as in mice expressing A152T-AAV. Therefore the current project will investigate the overall hypothesis that the A152T variant modulates disease risk through enhanced accumulation and increased solubility of pT153-positive tau, which subsequently primes tau for downstream pathological phosphorylation events and is critical for tau-mediated toxicity. Of note, phosphorylation on T153 and tau’s other serine/threonine-proline motifs has been shown to be required for tau toxicity, although the extent to which pT153 contributes to tau toxicity remains untested. In elucidating the pattern of pT153 deposition throughout the brain in A152T carriers and noncarriers, the proposed studies will determine if pT153-positivity coincides with neurodegeneration. Using site-directed mutagenesis and somatic brain transgenesis, we will determine whether pT153 is required for tau toxicity in vivo. Finally, incorporating rapidly evolving technology that is enabling acquisition of global gene expression profiles at the single cell level, we will assess whether expression of the A152T variant differentially impacts the transcriptome of individual cell populations. We anticipate that in uncovering the mechanisms by which A152T influences risk of tauopathy, and deciphering the involvement of pT153 in tau toxicity, the current project could identify novel approaches to block tau-mediated neurodegeneration in AD and related disorders.