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

A152T 风险变异与 tau 蛋白病之间联系的机制见解

• 批准号: 10601054
• 负责人: Casey N Cook
• 金额: $ 44.95万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601054
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Animal Model; Antibodies; Autopsy; Behavioral; Biochemical; Brain; Cells; Characteristics; Data; Dementia with Lewy Bodies; Deposition; Disease; Disease Marker; Disease Progression; Epitopes; Event; Gene Expression; Gene Transfer Techniques; Genes; Human; Individual; Link; Mass Spectrum Analysis; Mediating; Monitor; Mus; Mutation; Nerve Degeneration; Pathogenicity; Pathologic; Patients; Pattern; Phenotype; Phosphorylation; Population; Progressive Supranuclear Palsy; Proline; Risk; Risk Factors; Role; Sampling; Series; Serine; Site; Site-Directed Mutagenesis; Solubility; Tauopathies; Technology; Testing; Threonine; Toxic effect; Transcription Alteration; Variant; brain tissue; cell type; corticobasal degeneration; disease classification; disease phenotype; disorder risk; in vivo; insight; neuropathology; novel; novel strategies; prevent; promote resilience; risk variant; single nucleus RNA-sequencing; tau Proteins; tau function; tau mutation; tau-1; transcriptome

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.

tau基因（MAPT）中的致病性突变与tau蛋白病的发作有关，但A152 T突变在作为一系列疾病的风险因素方面是独特的，包括阿尔茨海默病（AD），进行性核上性麻痹（PSP），皮质基底节变性（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，我们推断，了解A152 T变体如何调节AD和相关疾病的风险可以揭示一种常见的疾病机制，揭示增加对tau毒性的恢复力并改变患者疾病表型的新策略。鉴于引入了一种新的潜在磷酸化表位，我们质疑A152 T变体是否可能通过改变T152或邻近T153残基上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，其揭示了与非携带者相比，来自A152 T携带者的死后脑组织中T153（pT 153）上过度磷酸化的可溶性tau种类的显著积累，以及在表达A152 T-AAV的小鼠中。因此，目前的项目将研究A152 T变体通过增强pT 153阳性tau的积累和增加其溶解度来调节疾病风险的总体假设，pT 153阳性tau随后引发tau下游病理性磷酸化事件，并且对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毒性所需的，尽管pT 153对tau毒性的贡献程度尚未测试。在阐明A152 T携带者和非携带者中pT 153在整个脑中沉积的模式时， 建议的研究将确定pT 153阳性是否与神经变性一致。使用定点诱变和体细胞脑转基因，我们将确定是否pT 153所需的tau毒性在体内。最后，结合快速发展的技术，能够在单细胞水平上获得全球基因表达谱，我们将评估A152 T变体的表达是否差异影响单个细胞群的转录组。我们预计，在揭示A152 T影响tau蛋白病风险的机制，并破译pT 153参与tau蛋白毒性的过程中，目前的项目可以确定阻断AD和相关疾病中tau蛋白介导的神经变性的新方法。