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(蛋白质稳态)对生物体的健康至关重要，它在衰老过程中的紊乱是基础。 年龄相关的神经退行性疾病。众所周知，阿尔茨海默病(AD)的病理机制是 与蛋白平衡紊乱有关，导致β-淀粉样蛋白(A？)聚集和过度磷酸化 陶先生。然而，目前还不清楚蛋白平衡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 在调节细胞动态平衡和机体健康方面起着至关重要的作用。溶酶体是高度新陈代谢的 具有活性，并含有各种专用于特定底物的水解酶。同时， 其他人和我们的研究也揭示了溶酶体的信号作用，这与新陈代谢密切相关 溶酶体的状态。另一方面，内质网对蛋白质合成是必不可少的，并利用质量控制 维持蛋白质平衡的机制。到目前为止，人们对溶酶体的机制仍知之甚少。 代谢和信号调节内质网蛋白平衡。在我们对秀丽线虫的研究中，我们有 发现一条新的溶酶体到细胞核的逆行信号通路，连接溶酶体的NADPH代谢 和ER蛋白平衡，也揭示了这种溶酶体信号在AD预防中的关键作用。 衰老。值得注意的是，这个溶酶体信号通路在分子、细胞和生化方面都具有保守性。 人类。在这项提议中，我们的目标是系统地破译该信号的溶酶体和核成分 在线虫中的途径，并阐明该途径是如何控制ER蛋白平衡和参与AD的 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 (线虫和小鼠)，将为理解溶酶体代谢和溶酶体的作用奠定基础 在人类健康和疾病方面的信号。这一项目的成功完成将促进我们的 目前关于溶酶体功能和信号在衰老和AD中的知识，开辟了一条新的途径 了解AD在衰老过程中的发病机制，对AD患者的防治具有重要意义 我们当前的社会和子孙后代。