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
基本信息
- 批准号:10485489
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AccelerationAddressAgeAgingAutophagocytosisBindingBioenergeticsBiogenesisBiosynthetic ProteinsBrainCell DeathCellsCessation of lifeComplexCytoprotectionDataDepositionDeteriorationDiseaseDisease OutcomeDisease ProgressionEnzymesEtiologyFamilyFibroblastsGeneral PopulationGeneticGlutamate-ammonia-ligase adenylyltransferaseGoalsGrantHousekeepingHumanHuntington DiseaseHuntington geneLengthMaintenanceMetabolicMetabolismMissionMitochondriaModelingMolecularMolecular ChaperonesMolecular TargetNerve DegenerationNeuronsNiacinamideNicotinamidaseNicotinic AcidsParkinson DiseasePathway interactionsPatientsPhysical PerformanceProteinsReportingResearchRoleSirtuinsStimulation of Cell ProliferationStressStructureStructure-Activity RelationshipSystemTestingTherapeutic InterventionToxic effectTranslationsUnited States Department of Veterans AffairsVeteransYeast Model SystemYeastsage relatedage related neurodegenerationalpha synucleincognitive performanceefficacy studyenzyme pathwayflyhealthspanin vivoinduced pluripotent stem cellinterdisciplinary approachmisfolded proteinmouse modelneuron lossneuroprotectionnicotinamide phosphoribosyltransferasenicotinamide-beta-ribosidenicotinatenicotinate mononucleotidenovelnovel therapeutic interventionoverexpressionpolyglutaminepostmitoticpreclinical efficacypreventprotein misfoldingproteostasisproteotoxicityrecruitresistance mechanismstem cell differentiationsynucleinopathytoolyeast protein
项目摘要
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
退伍军人及其家人的身体和/或认知能力随着
年龄。人类神经退行性蛋白质错误折叠障碍或蛋白质病与
脑神经元中蛋白质的异常沉积。它们包括多聚谷氨酰胺(PolyQ)疾病,如
亨廷顿氏病和帕金森氏病等α-突触核糖核病。披露基本信息
有丝分裂后细胞(如神经元)老化过程中发生的分子和代谢变化
蛋白毒性应激对于理解神经蛋白病的病因学至关重要。
代谢和线粒体的改变是衰老和神经退化的标志。超过了
在过去的十年里,我们和其他人已经表明,促进有丝分裂或过度表达
NMNAT/NMA1是烟酸/烟酰胺挽救NAD+生物合成途径中的一种酶,作用于
在酵母、苍蝇和小鼠模型中作为蛋白质毒性的强有力的抑制因子。通过酵母中的筛分
我们发现NAD+生物合成抢救途径的另外三种酶在
蛋白调控:Nads/Qns1、NaPTRase/Npt1和NDase/Pnc1。我们的观察表明
一种进化上保守的“重新利用”(或“兼职”)管家酶的策略
在压力条件下。在蛋白毒性胁迫下,这四种蛋白质被招募为分子。
具有保持酶和折叠酶活性的伴侣。在酵母细胞中,NAD+补救蛋白通过
防止错误折叠,并与Hsp90伴侣一起,促进延长的
多Q结构域或α-突触核蛋白。它们的催化功能不是其伴侣作用所必需的。
在人类神经元模型中的初步研究表明,人类蛋白质保存
类似的“兼职”功能和抵御蛋白毒性应激的能力。
我们现在建议解决的根本问题是
人类神经元的代谢和细胞蛋白质动态平衡途径。我们的一些研究将
继续利用酵母模型进行结构-功能关系研究,以揭示
参与四种酵母蛋白伴侣功能的结构域。我们还将继续使用酵母
在烟酰胺核苷补救NAD+生物合成中筛选抑制子的HD模型
途径酶。我们研究的一个重要组成部分是对先前结果的翻译
在酵母中获得HD患者来源的神经元和HD小鼠模型。两种神经元培养系统
将用于测试疾病进展的不同方面:HD患者衍生的诱导多能性
干细胞(IPSCs)通过直接诱导分化为神经元和HD患者来源的神经元
成纤维细胞的转化。表达全长亨廷顿蛋白的小鼠模型将用于临床前
体内药效研究。我们假设线粒体生物发生和NAD+生物合成蛋白
途径分别在促进能量稳定和维持蛋白稳定方面发挥相加作用,在
这样,就可以保护HD神经元免于死亡。
识别和表征神经保护意愿的独立但协同的途径
揭示神经保护的复杂网络以及新陈代谢和
神经退行性变。这项拟议的研究可能会导致新的治疗方法来调节
这些途径可以中和细胞毒性,延长健康寿命。最后,控制的能力
抗蛋白毒性胁迫等抗逆机制可能提供分子靶标
以及治疗退伍军人和普通人群的工具,以增强他们的身体和认知能力
并延缓其随着年龄的增长而逐渐恶化。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Antoni Barrientos其他文献
Antoni Barrientos的其他文献
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{{ truncateString('Antoni Barrientos', 18)}}的其他基金
The Biosynthetic Pathway of Mitochondrial Respirasomes
线粒体呼吸体的生物合成途径
- 批准号:
8995666 - 财政年份:2014
- 资助金额:
-- - 项目类别:
FASEB SRC on Mitochondrial Assembly & Dynamics in Health, Disease & Aging
FASEB SRC 线粒体组装
- 批准号:
8199803 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Cytochrome c Oxidase Assembly in Health and Disease
健康和疾病中的细胞色素 c 氧化酶组装
- 批准号:
8237711 - 财政年份:2006
- 资助金额:
-- - 项目类别:
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