Prostaglandin J2 -regulated pathways critical for aggregation of ubiquitinated proteins and neurodegeneration in a cellular model of neuroinflammation.
Item
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Title
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Prostaglandin J2 -regulated pathways critical for aggregation of ubiquitinated proteins and neurodegeneration in a cellular model of neuroinflammation.
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Identifier
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AAI3169994
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identifier
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3169994
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Creator
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Wang, Zhiyou.
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Contributor
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Adviser: Maria E. Figueiredo-Pereira
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Date
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2005
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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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Chemistry, Biochemistry | Biology, Neuroscience | Biology, Cell
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Abstract
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Most neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), are characterized by two hallmarks: the progressive loss of neuronal cells and the presence of inclusion bodies with aggregates of ubiquitinated proteins. However, the cellular and molecular mechanisms responsible for these two pathological characteristics remain elusive. In particular, the pathogenic role of the inclusion bodies is still widely debated.;The research described in this project addresses the hypothesis that inflammation may be a major contributor to both neuronal death and aggregation of ubiquitinated proteins that occur in neurodegeneration. Two experimental approaches were undertaken to investigate this hypothesis: (1) To address the impact of inflammation on neuronal cells we treated human neuroblastoma SK-N-SH cells with prostaglandin J2 (PGJ2), an endogenous product of inflammation. Through high-throughput genomic and proteomic approaches we identified intracellular pathways affected by PGJ2 that may be relevant to neurodegeneration. Some of these pathways include the heat shock response, the ubiquitin/proteasome pathway and mitochondrial energy production. (2) To establish mechanisms implicated in the aggregation of ubiquitinated proteins detected in neurodegenerative disorders we focused on the sequestosome-1/p62. The latter is a protein containing a ubiquitin associated domain (UBA) at its C-terminus which confers the ability to bind polyubiquitinated proteins non-covalently. We found that PGJ2 up-regulates sequestosome 1/p62 in a time- and dose-dependent manner in human neuroblastoma SK-N-SH cells. Preventing sequestosome 1/p62 up-regulation by RNA interference abolished the aggregation but not the accumulation of ubiquitinated proteins nor PGJ2-cytotoxicity.;In conclusion, these findings support the hypothesis that for many neurodegenerative diseases for which the root cause is unknown, products of neuroinflammation, such as PGJ2, may play a key role. Furthermore, sequestosome 1/p62 up-regulation under stress conditions, such as those induced by PGJ2, contributes to the "sequestration" of poly-ubiquitinated proteins into aggregates. However, the overwhelming accumulation of ubiquitinated proteins, rather than their aggregation, is likely to be an important contributor to neuronal death.
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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.
