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大脑疾病，会导致进行性记忆丧失和认知能力下降，是痴呆症的头号原因。它的特点是细胞外淀粉样斑块(主要由淀粉样β-42(Abeta)多肽形成)和细胞内含有异常tau聚集体的神经纤维缠结共存。多年来，Abeta和tau一直被认为是相互脱节的罪魁祸首，但最近的研究表明，它们密切相关，具有协同作用。遗憾的是，人们对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方法的发展。为了解决这个问题，我们产生了一种新的AD苍蝇模型，它在基因上同时产生人类Abeta和tau，从而导致协同病理。这些果蝇显示出细胞外沉积的硫代黄素-S阳性的Abeta，细胞内野生型tau的聚集和磷酸化，以及神经细胞的进行性丢失。这些果蝇的强大和一致的病理学为基因发现工作提供了一个独特的机会，因此我们在果蝇眼中进行了大规模的功能丧失RNAi筛查，这提供了一个有用的和易于评分的表型。在测试的6,600个RNAi库中，我们确定了31个抑制子和119个增强子，包括多个以前未知的与AD相关的基因。大多数抑制子与蛋白质修饰或切割、核糖体功能、细胞代谢、转录、染色质调节和运输有关，仅举几例。在这里，我们将采用战略性设计的管道，将遗传学与高通量行为平台和目标优先顺序相结合，以确定疾病的强大晚期修饰物(目标1)。另一方面，我们将快速追踪一个最强的抑制子及其人类同源物的机械和治疗分析(目标2)。这个抑制子编码了一种高度无序的蛋白质，功能不明，在我们进行的另外两次遗传筛查中也发现了这种蛋白质。因此，我们将其列为高度优先的目标。我们坚信，这里提出的150种Abeta+tau毒性修饰剂的操作将为新的靶点或疗法提供基础。因此，这项工作可能会对解决阿尔茨海默氏症的国家计划的目标做出重大贡献。