Characterization of the 26S proteasome in Drosophila melanogaster as a model for aging.
Item
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Title
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Characterization of the 26S proteasome in Drosophila melanogaster as a model for aging.
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Identifier
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AAI3284379
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identifier
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3284379
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Creator
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Vernace, Vita A.
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Contributor
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Adviser: Maria Figueiredo-Pereira
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Date
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2007
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Neuroscience
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Abstract
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In all cells, protein degradation is a constant process that is critical for cell survival and repair. It ensures that damaged proteins are degraded and that all proteins needed by the cells for a variety of functions are available at the right time and in the right amounts.;The ubiquitin-proteasome pathway (UPP) is the major proteolytic pathway that degrades intracellular proteins. It plays critical roles in many cellular processes and diseases. Disruption of the UPP is particularly relevant to pathophysiological conditions that provoke the accumulation of aberrant proteins, such as in aging as well as in a variety of neurodegenerative disorders.;We hypothesize that one of the reasons why these neurodegenerative conditions exhibit a late onset is because proteasome activity decreases with aging. Aging-dependent impairment in proteolysis mediated by the proteasome may have profound ramifications for cell viability. It can lead to, for example, the accumulation of modified, potentially toxic proteins in cells and can cause tissue inflammation as well as premature cell death by apoptosis or necrosis.;To address this hypothesis, the major aim of this thesis was to identify mechanisms mediating the aging-dependent impairment of the proteasome in an in vivo setting, by using Drosophila as a model. Our studies revealed that: (1) The activity of the 26S proteasome declines significantly when the flies reach an age at which overall ATP levels are highly reduced; (2) The decline in 26S proteasome activity observed in Drosophila is not a gradual process and (3) The sharp deficit in 26S proteasome activity observed in the "old" flies increases their sensitivity to proteotoxic stress.;Our results provide strong evidence for considering ATP reduction in conjunction with 26S proteasome impairment as aging hallmarks. In addition, they suggest that an "old" age deficit in 26S proteasome activity may contribute to the late onset observed in most human neurodegenerative.;The experimental approaches used in this thesis take advantage of the power of a simple in vivo model system, like Drosophila , to obtained critical information on the effects of aging on protein turnover associated with the ubiquitin-proteasome pathway.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
