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Principal Investigator: Kevin Chui
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2024
Award: $39,884
Funding agency: National Institute on Aging
Project Summary
The incidence of age-related diseases such as Alzheimer’s disease and Parkinson’s disease continues to
increase as human lifespan continues to increase. Advancements in science and healthcare have resulted in
effective therapies for many diseases but treatments for these debilitating diseases remain elusive. Many studies
on aging focus on the dysfunction of basic cellular processes, or the hallmarks of aging. These include
mitochondrial dysfunction, abnormal nutrient signaling, telomere shortening, amongst many others. We recently
found that lysosomal (vacuole in yeast) deacidification is an early event in aging and precedes mitochondrial
dysfunction. Vacuole deacidification results in a loss of amino acid compartmentalization, particularly cysteine,
and this results in mitochondrial dysfunction. Amino acid restriction or supplementation with iron rescued
mitochondrial function. These previous findings demonstrate the importance of the vacuole in amino acid
homeostasis and aging. It should be noted that vacuole deacidification is a gradual process in aging and there
are likely systems that collaborate with the vacuole in maintaining cellular homeostasis. Thus, we performed a
screen to determine what genes are conditionally essential upon vacuole deacidification. We uncovered genes
involved in the ESCRT/MVB pathway as essential under these conditions. Furthermore, we also found several
genes involved in endocytosis to be conditionally essential too. The ESCRT pathway is a cellular trafficking
pathway that allows for the remodeling of the plasma membrane (PM) proteome, especially nutrient transporters.
When transporters are endocytosed, the ESCRT pathway recognizes ubiquitylated transporters and directs them
to the vacuole for degradation. The known function of the ESCRT pathway in conjunction with the vacuole’s role
in amino acid compartmentalization raises the idea that these two systems collaborate in maintaining cellular
amino acid homeostasis during the aging process. This is supported by our pilot study showing that amino acid
transporters (AATs) are indeed endocytosed upon vacuole deacidification. By using the budding yeast
Saccharomyces cerevisiae, we will determine how amino acid uptake and metabolite pools are affected under
conditions of vacuole deacidification. Furthermore, we will elucidate the signal that originates from dysfunctional
vacuoles that triggers AAT endocytosis and turnover. Finally, we will test the hypothesis that Aβ inhibits ESCRT-
mediated turnover of AATs and inhibits cell growth by causing amino acid toxicity. Aging remains an active field
of research but how the ESCRT pathway cooperates with the vacuole in the context of aging is understudied.
Furthermore, how Aβ expression affects cellular amino acid homeostasis is understudied. The goal of this
proposal is to elucidate a novel mechanism for cellular aging and increase our understanding of the pathogenesis
of Alzheimer’s disease.
Terms: <AD dementia><AD model><Acidity><Acids><Active Oxygen><Affect><Age><Aging><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease model><Alzheimers Dementia><Amino Acid Channel><Amino Acid Transport Systems><Amino Acid Transporter><Amino Acids><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β toxicity><Amyloid β-Peptide><Amyloid β-Protein><Area><Assay><Autoregulation><Aβ><Baker's Yeast><Bioassay><Bioavailability><Biological Assay><Biological Availability><Brewer's Yeast><Budding Yeast><Calcium ion><Cancers><Catabolism><Cell Aging><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Protection><Cell Senescence><Cell Signaling><Cell Survival><Cell Viability><Cell membrane><Cells><Cellular Aging><Cellular Expansion><Cellular Function><Cellular Growth><Cellular Metabolic Process><Cellular Physiology><Cellular Process><Cellular Senescence><Collaborations><Cysteine><Cytoplasm><Cytoplasmic Membrane><Cytoprotection><Development><Disease><Disorder><Down-Regulation><Drug Targeting><Drugs><Dysfunction><Endocytosis><Endomycetales><Endoplasmic Reticulum><Ergastoplasm><Event><Fe element><Functional disorder><Generalized Growth><Genes><Goals><Growth><Half-Cystine><Haploid><Haploidy><Healthcare><Homeostasis><Human><ICP-MS><Immunoblotting><Incidence><Individual><Inductively Coupled Plasma Mass Spectrometry><Intermediary Metabolism><Intracellular Communication and Signaling><Iron><L-Cysteine><Link><Lysosomes><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Medication><Membrane Transport Proteins><Membrane Transporters><Metabolic Processes><Metabolism><Microscopy><Mitochondria><Modern Man><Multivesicular Body><Nature><Nutrient><Organelles><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxygen Radicals><Paralysis Agitans><Parkinson><Parkinson Disease><Pathogenesis><Pathway interactions><Pharmaceutical Preparations><Physiologic Availability><Physiological Homeostasis><Physiopathology><Pilot Projects><Plasma Membrane><Play><Primary Parkinsonism><Primary Senile Degenerative Dementia><Pro-Oxidants><Process><Proteins><Proteome><Reactive Oxygen Species><Regulation><Replicative Senescence><Research><Role><S cerevisiae><S. cerevisiae><Saccharomyces cerevisiae><Saccharomycetales><Science><Signal Transduction><Signal Transduction Systems><Signaling><Site><Structure><Subcellular Process><Supplementation><System><Telomere Shortening><Testing><Tissue Growth><Toxic effect><Toxicities><V-ATPase><V-type ATPase><Vacuole><Western Blotting><Western Immunoblotting><Yeast Model System><Yeasts><a beta peptide><abeta><abeta toxicity><age associated><age associated disease><age associated disorder><age associated impairment><age correlated><age dependent><age dependent disease><age dependent disorder><age dependent impairment><age linked><age related><age related human disease><age specific><age-related disease><age-related disorder><age-related impairment><ages><aging associated><aging process><aging related><alzheimer model><aminoacid><amyloid beta><amyloid beta toxicity><amyloid-b protein><aβ toxicity><beta amyloid fibril><biological signal transduction><cell age><cell growth><cell metabolism><cellular age><cellular metabaolism><cytoprotective><deletion collection><deletion library><developmental><drug/agent><effective therapy><effective treatment><experiment><experimental research><experimental study><experiments><fat metabolism><hallmarks of aging><health care><innovate><innovation><innovative><life span><lifespan><lipid metabolism><lysosome membrane><macromolecule><malignancy><mitochondrial><mitochondrial dysfunction><mutant><neoplasm/cancer><novel><ontogeny><pathophysiology><pathway><pillars of aging><pilot study><plasmalemma><primary degenerative dementia><protein blotting><response><senile dementia of the Alzheimer type><social role><soluble amyloid precursor protein><telomere attrition><tool><trafficking><uptake><vacuolar ATPase><vacuolar H+-ATPase><vacuolar membrane H(+)-ATPase><yeast model>