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的健康寿命
项目成果
期刊论文数量(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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