Slowing proteotoxic neurodegeneration by boosting mitochondrial bioenergetics and recruiting a novel class of chaperones

通过增强线粒体生物能和招募一类新型伴侣来减缓蛋白毒性神经变性

• 批准号: 10485489
• 负责人: Antoni Barrientos
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485489
• 关键词: Acceleration; Address; Age; Aging; Autophagocytosis; Binding; Bioenergetics; Biogenesis; Biosynthetic Proteins; Brain; Cell Death; Cells; Cessation of life; Complex; Cytoprotection; Data; Deposition; Deterioration; Disease; Disease Outcome; Disease Progression; Enzymes; Etiology; Family; Fibroblasts; General Population; Genetic; Glutamate-ammonia-ligase adenylyltransferase; Goals; Grant; Housekeeping; Human; Huntington Disease; Huntington gene; Length; Maintenance; Metabolic; Metabolism; Mission; Mitochondria; Modeling; Molecular; Molecular Chaperones; Molecular Target; Nerve Degeneration; Neurons; Niacinamide; Nicotinamidase; Nicotinic Acids; Parkinson Disease; Pathway interactions; Patients; Physical Performance; Proteins; Reporting; Research; Role; Sirtuins; Stimulation of Cell Proliferation; Stress; Structure; Structure-Activity Relationship; System; Testing; Therapeutic Intervention; Toxic effect; Translations; United States Department of Veterans Affairs; Veterans; Yeast Model System; Yeasts; age related; age related neurodegeneration; alpha synuclein; cognitive performance; efficacy study; enzyme pathway; fly; healthspan; in vivo; induced pluripotent stem cell; interdisciplinary approach; misfolded protein; mouse model; neuron loss; neuroprotection; nicotinamide phosphoribosyltransferase; nicotinamide-beta-riboside; nicotinate; nicotinate mononucleotide; novel; novel therapeutic intervention; overexpression; polyglutamine; postmitotic; preclinical efficacy; prevent; protein misfolding; proteostasis; proteotoxicity; recruit; resistance mechanism; stem cell differentiation; synucleinopathy; tool; yeast protein

One of the major challenges for the U.S. Department of Veterans Affairs is to extend the health-span of the veterans and their families as their physical and/or cognitive performance capabilities decline with age. Human neurodegenerative protein misfolding disorders or proteinopathies, are associated with abnormal protein depositions in brain neurons. They include polyglutamine (polyQ) disorders such as Huntington's disease and α-synucleinopathies such as Parkinson's disease. Disclosing the basic molecular and metabolic alterations that occur during aging of post-mitotic cells such as neurons, under proteotoxic stress is crucial for understanding the etiology of neuro-proteinopathies. Metabolic and mitochondrial alterations are hallmarks of aging and neurodegeneration. Over the last decade, we and others have shown that enhancement of mitogenesis or overexpression of NMNAT/NMA1, an enzyme in the Nicotinic acid/Nicotinamide Salvage NAD+ biosynthetic pathway, act as powerful suppressor of proteotoxicities in yeast, fly and mouse models. Through screens in yeast models we identified three additional enzymes of the NAD+ biosynthetic salvage pathway with a role in proteostasis: NADS/Qns1, NaPTRase/Npt1 and NDase/Pnc1. Our observations suggest the existence of an evolutionarily conserved strategy of `repurposing' (or `moonlighting') housekeeping enzymes under stress conditions. Under proteotoxic stress, the four proteins are recruited as molecular chaperones with holdase and foldase activities. In yeast cells, the NAD+ salvage proteins act by preventing misfolding and, together with the Hsp90 chaperone, promoting the refolding of extended polyQ domains or α-synuclein. Their catalytic function is not required for their chaperone role. Preliminary studies in human neuronal models of HD have shown that the human proteins conserve similar “moonlighting” functions and the capacity to protect against proteotoxic stress. We now propose to address the fundamental problem of the intricate interaction between metabolic and cellular protein homeostasis pathways in human neurons. Some of our studies will continue exploiting the yeast model to perform structure-function relationship studies to disclose the domains involved in the chaperone function of the four yeast proteins. We will also continue using yeast models of HD to screen for suppressors among the Nicotinamide Riboside Salvage NAD+ biosynthetic pathway enzymes. An essential component of our studies is the translation of the results previously obtained in yeast to HD patient-derived neurons and HD mouse models. Two neuronal culture systems will be used to test different aspects of disease progression: HD patient-derived induced pluripotent stem cells (iPSCs) differentiated into neurons and HD patient-derived neurons through direct conversion of fibroblasts. A mouse model expressing full-length huntingtin will be used for pre-clinical efficacy studies in vivo. We hypothesize that mitochondrial biogenesis- and NAD+ -biosynthetic-protein pathways act additively to promote energetic stability and maintain proteostasis, respectively, and in this way, protect HD neurons against death. Identifying and characterizing independent yet synergistic pathways of neuroprotection will reveal the complex network for neuroprotection and the intricate relationship between metabolism and neurodegeneration. The proposed research may lead to novel therapeutic approaches to modulate these pathways to counteract cellular toxicities and extend health-span. Finally, the ability to control stress-resistance mechanisms such as those against proteotoxic stress may provide molecular targets and tools to treat the Veterans and the general population to enhance their physical and cognitive performance and postpone their progressive deterioration with age.

美国退伍军人事务部面临的主要挑战之一是延长退伍军人的健康寿命