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.

摘要 蛋白质稳态对机体的健康至关重要，而衰老过程中蛋白质稳态的紊乱是 与年龄相关的神经退行性疾病。众所周知，阿尔茨海默病（AD）的病理是 与蛋白质稳态的破坏有关，导致β-淀粉样蛋白（A β）的聚集和过度磷酸化 τ的然而，目前尚不清楚蛋白质稳态被破坏的细胞和分子机制， AD在老化过程中。溶酶体和内质网是两组细胞器， 在调节细胞稳态和有机体健康方面起着至关重要的作用。溶酶体是高度代谢的 具有活性并含有各种专用于水解特定底物的酶。与此同时，委员会认为， 其他人和我们的研究也揭示了溶酶体的信号作用，这与代谢密切相关。 溶酶体的状态。另一方面，ER是蛋白质合成所必需的，并利用质量控制 维持蛋白质稳态的机制。到目前为止，人们对溶酶体如何机械地 代谢和信号传导调节ER蛋白稳态。在我们使用秀丽隐杆线虫的研究中， 发现了一种新的溶酶体到细胞核的逆行信号通路， 和ER蛋白质稳态，并揭示了这种溶酶体信号传导在AD预防中的关键作用， 衰老引人注目的是，这种溶酶体信号通路在细胞内进行分子，细胞和生化保守。 人类在这个建议中，我们的目标是系统地破译这种信号的溶酶体和核成分 C. elegans，并阐明这一途径如何控制ER蛋白稳态，并有助于AD 哺乳动物神经系统的发病机制。拟议的研究尽管是在动物模型中设计的 （C. elegans和小鼠），将为理解溶酶体代谢和溶酶体 信号在人类健康和疾病中的作用这个项目的成功完成将促进我们的 目前关于溶酶体功能和衰老和AD信号传导的知识，为研究溶酶体功能和信号传导开辟了新的途径。 了解老年性痴呆的发病机制，为老年性痴呆患者的预防和治疗提供参考。 我们现在的社会和未来的世代。