Harnessing new targets and mechanisms mediating AD pathogenesis

利用介导 AD 发病机制的新靶点和机制

• 批准号: 10590789
• 负责人: Diego E Rincon-Limas
• 金额: $ 36.84万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590789
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-42; Autophagocytosis; Behavioral; Behavioral Assay; Binding; Biological Assay; Brain Diseases; C9ORF72; Cell Cycle; Cellular Metabolic Process; Chromatin; Collection; Complex; Cytoskeletal Proteins; Data; Data Set; Dementia; Deposition; Development; Dipeptides; Disease; Disease Progression; Drosophila genus; Elderly; Enhancers; Ensure; Eye; Foundations; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Homeostasis; Homologous Gene; Human; Impaired cognition; Label; Link; MJD1 protein; Mediating; Memory Loss; Molecular; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Ontology; Other Genetics; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pattern; Peptides; Phenotype; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Property; Proteins; Proteolysis; Public Health; RNA Interference; RNA Splicing; RNA interference screen; Reporting; Research; Ribosomes; Role; Senile Plaques; System; Testing; Therapeutic; Thioflavin S; Time; Toxic effect; Ubiquitination; Work; candidate validation; deletion analysis; design; effective therapy; extracellular; flexibility; fly; gene discovery; hyperphosphorylated tau; loss of function; neuron loss; neuropathology; neuroprotection; neurotoxic; novel; prevent; protein TDP-43; tau Proteins; tau interaction; tau mutation; tool

Alzheimer’s disease (AD) is an incurable neurodegenerative brain disorder that causes progressive memory loss and cognitive decline, and is the No.1 cause of dementia. It is characterized by the coexistence of extracellular amyloid plaques, mainly formed by the amyloid beta-42 (Abeta) peptide, and intracellular neurofibrillary tangles containing aggregates of abnormal tau. Abeta and tau were considered as disconnected culprits for many years, but in view of recent studies, it is clear that they are intimately related and possess synergistic activities. Sadly, very little is known about how Abeta and tau interactions trigger AD pathogenesis, which significantly hinders the development of effective treatments. To address this, we generated a new fly model of AD that genetically produces both human Abeta and tau resulting in synergistic pathology. These flies display extracellular deposits of thioflavin-S-positive Abeta, intracellular aggregation and phosphorylation of wild-type tau, and progressive loss of neuronal cells. The robust and consistent pathology of these flies provides a unique opportunity for gene discovery efforts and thus we performed a massive loss-of-function RNAi screen in the fly eye, which provides a useful and easy-to-score phenotype. Out of 6,600 RNAi stocks tested, we identified 31 suppressors and 119 enhancers, including multiple genes not previously known to be associated with AD. Most suppressors are linked to protein modification or cleavage, ribosomal function, cell metabolism, transcription, chromatin modulation, and transport to name a few. Here, we will employ a strategically designed pipeline that integrates genetics with high-throughput behavioral platforms and target prioritization to identify robust late-stage modifiers of the disease (Aim 1). On the other hand, we will fast-track a mechanistic and therapeutic analysis of one of the strongest suppressors along with its human homologue (Aim 2). This suppressor encodes a highly disordered protein of uncharacterized function and was also found in two other genetic screens performed by us. Thus, we have labelled it as a high-priority target. We strongly believe that manipulation of the 150 modifiers of Abeta+tau toxicity presented here will provide the foundation for new types of targets or therapeutics. Therefore, this work may contribute significantly to the goals of the National Plan to Address Alzheimer’s Disease.

阿尔茨海默病（AD）是一种无法治愈的神经退行性脑疾病，导致进行性记忆丧失和认知能力下降，是痴呆症的头号病因。其特征在于主要由淀粉样蛋白β-42（Abeta）肽形成的细胞外淀粉样蛋白斑块和含有异常tau聚集体的细胞内神经元缠结的共存。多年来，Abeta和tau被认为是不相关的罪魁祸首，但鉴于最近的研究，很明显，它们是密切相关的，并具有协同作用。可悲的是，关于Abeta和tau相互作用如何触发AD发病机制知之甚少，这严重阻碍了有效治疗的发展。为了解决这个问题，我们产生了一种新的AD果蝇模型，该模型在遗传上产生人Abeta和tau，从而导致协同病理学。这些果蝇表现出硫磺素-S阳性Abeta的细胞外沉积、野生型tau的细胞内聚集和磷酸化以及神经元细胞的进行性丧失。这些苍蝇强大且一致的病理学为基因发现工作提供了独特的机会，因此我们在苍蝇眼睛中进行了大规模的功能丧失RNAi筛选，这提供了有用且易于评分的表型。在测试的6,600个RNAi库存中，我们确定了31个抑制子和119个增强子，包括以前不知道与AD相关的多个基因。大多数抑制因子与蛋白质修饰或切割、核糖体功能、细胞代谢、转录、染色质调节和转运相关，仅举几例。在这里，我们将采用一个战略性设计的管道，将遗传学与高通量行为平台和目标优先级相结合，以识别疾病的强有力的晚期修饰因子（目标1）。另一方面，我们将快速跟踪一个最强的抑制剂之一的机制和治疗分析沿着其人类同源物（目标2）。这种抑制基因编码一种高度无序的蛋白质，其功能不明，并且在我们进行的另外两种遗传筛选中也被发现。因此，我们将其列为高度优先目标。我们坚信，对本文所述的150种Abeta+tau毒性修饰剂的操纵将为新型靶标或治疗方法提供基础。因此，这项工作可能会大大有助于解决阿尔茨海默病的国家计划的目标。