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: 10374879
• 负责人: Casey N Cook
• 金额: $ 59.03万
• 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/10374879
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease risk; Animal Model; Antibodies; Autopsy; Behavioral; Biochemical; Brain; Cell Nucleus; Cells; Characteristics; Data; Dementia with Lewy Bodies; Deposition; Disease; Disease Marker; Disease Progression; Epitopes; Event; Gene Expression; Gene Transfer Techniques; Genes; Human; Individual; Light; 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; base; brain tissue; cell type; corticobasal degeneration; disease phenotype; disorder risk; in vivo; insight; mutation carrier; novel; novel strategies; prevent; resilience; risk variant; tau Proteins; tau function; tau mutation; tau phosphorylation; transcriptome; transcriptome sequencing

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) 的致病性突变与 tau 蛋白病的发病有关，但 A152T 突变是独特的，它是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 在神经退行性疾病中作用的非常规方法，我们推断，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，揭示增强对 tau 毒性的抵抗力并改变患者疾病表型的新策略。鉴于引入了新的潜在磷酸表位，我们质疑 A152T 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。一系列新的抗体被产生来测试这个想法，结果表明，与非携带者以及表达 A152T-AAV 的小鼠相比，A152T 携带者死后脑组织中 T153 (pT153) 过度磷酸化的可溶性 tau 物种显着积累。因此，当前的项目将研究总体假设，即 A152T 变体通过增强 pT153 阳性 tau 的积累和增加溶解度来调节疾病风险，这随后为下游病理性磷酸化事件启动 tau，并且对于 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 毒性的贡献程度尚未测试。在阐明 A152T 携带者和非携带者大脑中 pT153 沉积的模式时， 拟议的研究将确定 pT153 阳性是否与神经变性一致。通过定点诱变和体细胞脑转基因，我们将确定 pT153 是否是体内 tau 毒性所必需的。最后，结合快速发展的技术，能够在单细胞水平获取全局基因表达谱，我们将评估 A152T 变体的表达是否对单个细胞群的转录组产生差异性影响。我们预计，通过揭示 A152T 影响 tau 蛋白病风险的机制，并破译 pT153 在 tau 毒性中的作用，当前的项目可以找到阻止 AD 和相关疾病中 tau 介导的神经变性的新方法。