Lysosomal NADPH metabolism regulates proteostasis, aging and tauopathy

溶酶体 NADPH 代谢调节蛋白质稳态、衰老和 tau 蛋白病

• 批准号: 10316880
• 负责人: Weiwei Dang
• 金额: $ 159.15万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-05 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316880
• 关键词: AD transgenic mice; Active Sites; Address; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Animal Model; Attenuated; Binding; Biochemical; Bioinformatics; Biology of Aging; Brain; Caenorhabditis elegans; Cell Nucleus; Cells; ChIP-seq; Development; Disease; Disease Progression; Elderly; Endoplasmic Reticulum; Enzymes; Epigenetic Process; FRAP1 gene; Functional disorder; Future Generations; Gene Expression; Genes; Genetic Transcription; Health; Histones; Homeostasis; Homologous Gene; Human; Hydrolysis; Knockout Mice; Knowledge; Light; Link; Longevity; Lysosomes; Mediating; Metabolic; Metabolism; Methods; Molecular; Mus; Mutation; NADP; Nervous system structure; Neurodegenerative Disorders; Neurons; Nuclear; Nuclear Hormone Receptors; Organelles; Organism; Pathogenesis; Pathologic; Pathway interactions; Phosphoric Monoester Hydrolases; Physiological; Play; Post-Translational Protein Processing; Prevention; Process; Promoter Regions; Protein Biosynthesis; Proteins; Proteome; Proteomics; Public Health; Quality Control; RNA interference screen; Regulation; Resolution; Role; Signal Pathway; Signal Transduction; Societies; Tauopathies; Time; Transcriptional Regulation; abeta accumulation; base; biological adaptation to stress; design; detection of nutrient; effective therapy; endoplasmic reticulum stress; extracellular; fitness; fluorescence lifetime imaging; healthspan; healthy aging; hyperphosphorylated tau; improved; innovation; insight; loss of function mutation; metabolomics; microscopic imaging; mouse model; novel; nucleotide metabolism; prevent; protective effect; protein aggregation; proteostasis; response; transcriptome; transcriptome sequencing; vacuolar H+-ATPase

Abstract Protein homeostasis (proteostasis) is crucial for organism fitness, and its disturbance during aging underlies age-associated neurodegenerative diseases. It is well known that the pathology of Alzheimer’s disease (AD) is associated with disruption of proteostasis, leading to aggregation of ß-amyloid (Aß) and hyperphosphorylated Tau. However, it remains unclear the cellular and molecular mechanism by which proteostasis is disrupted by AD during the aging process. Lysosomes and endoplasmic reticulum (ER) are two groups of organelles that play crucial roles in regulating cellular homeostasis and organismal health. Lysosomes are highly metabolic active and contain various enzymes dedicated to the hydrolysis of specific substrates. At the same time, others’ and our studies also reveal the signaling role of lysosomes, which is tightly linked with the metabolic status of the lysosome. On the other hand, ER is essential for protein synthesis and utilizes quality control mechanisms to maintain proteostasis. To date, it remains poorly understood how mechanistically lysosomal metabolism and signaling regulate ER proteostasis. In our studies using Caenorhabditis elegans, we have discovered a novel lysosome-to-nucleus retrograde signaling pathway that links lysosomal NADPH metabolism and ER proteostasis, and also revealed the crucial role of this lysosomal signaling in AD prevention during aging. Strikingly, this lysosomal signaling pathway carries molecular, cellular and biochemical conservation in human. In this proposal, we aim to systemically decipher lysosomal and nuclear components of this signaling pathway in C. elegans, and to elucidate how this pathway controls ER proteostasis and contributes to AD pathogenesis in the mammalian nervous system. The proposed studies, although designed in animal models (C. elegans and mice), will set a stage for understanding the role of lysosomal metabolism and lysosomal signaling in human health and diseases. The successful accomplishment of this project will advance our current knowledge regarding lysosomal function and signaling in aging and AD, open a new avenue for understanding AD pathogenesis during aging, and shed light on the prevention and treatment of AD patients in our current society and future generations.

抽象的 蛋白质稳态（蛋白质稳定）对于有机体健身至关重要，其衰老的灾难是至关重要的 与年龄相关的神经退行性疾病。众所周知，阿尔茨海默氏病（AD）的病理是 与蛋白质量的破坏有关，导致β-淀粉样蛋白（Aß）和高磷酸化的聚集 tau。然而，尚不清楚通过蛋白质抑制的细胞和分子机制被破坏 在老化过程中广告。溶酶体和内质网（ER）是两组细胞器 在控制细胞稳态和有机健康方面发挥关键作用。溶酶体高度代谢 活性并包含用于特定底物水解的各种酶。同时， 其他人和我们的研究也揭示了溶酶体的信号传导作用，这与代谢密切相关 溶酶体的状态。另一方面，ER对于蛋白质合成至关重要，并利用质量控制 维持蛋白质的机制。迄今为止，它仍然不太了解机械溶酶体 代谢和信号传导调节ER蛋白质。在我们使用秀丽隐杆线虫的研究中，我们有 发现了一种新型的溶酶体到核曲线逆行信号传导途径，该途径连接了溶酶体NADPH代谢 和ER蛋白质抗体，还揭示了该溶酶体信号在AD预防中的关键作用 老化。令人惊讶的是，这种溶酶体信号通路在 人类。在此提案中，我们的目标是系统地破译该信号的溶酶体和核成分 秀丽隐杆线虫中的途径，并阐明该途径如何控制ER蛋白质症并有助于AD 哺乳动物神经系统的发病机理。拟议的研究虽然在动物模型中设计 （秀丽隐杆线虫和小鼠）将设定一个阶段，以理解溶酶体代谢和溶酶体的作用 人类健康和疾病中的信号。该项目的成功成就将推动我们的 有关衰老和广告中溶酶体功能和信号传导的当前知识，开辟了新的途径 了解衰老期间的AD发病机理，并阐明AD患者的预防和治疗 我们当前的社会和后代。