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Expression and function of SIRT1, SIRT4, and glutamate dehydrogenase 1 within the central nervous system
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Komlos, Daniel. Expression and function of SIRT1, SIRT4, and glutamate dehydrogenase 1 within the central nervous system. Retrieved from https://doi.org/doi:10.7282/T3XG9Q63

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TitleExpression and function of SIRT1, SIRT4, and glutamate dehydrogenase 1 within the central nervous system
NameKomlos, Daniel (author); Pintar, John E (chair); Firestein, Bonnie L (internal member); Alder, Janet (internal member); Liu, Alice YC (internal member); Zhou, Renping (internal member); Cai, Li (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2011
Other Date2011-10 (degree)
SubjectNeuroscience, Glutamate dehydrogenase, Central nervous system—Metabolism
Extentx, 192 p. : ill.
DescriptionGlutamate dehydrogenase 1 (GDH1) reversibly interconverts glutamate and α-ketoglutarate, and although it has shown to have significant importance in metabolic functions within various organ systems, its function within the central nervous system has yet to be fully described. GDH1 is allosterically regulated by many factors, and has been shown to be inhibited by the ADP-ribosyltransferase SIRT4, a mitochondrially localized sirtuin with unknown expression in the brain. We show that GDH1, along with SIRT4, are mitochondrially localized within the brain, that GDH1 is expressed in astrocytes in the postnatal brain and that SIRT4 is expressed in radial glia during embryonic tissues and appears to decrease in expression during development. We show that in radial glial cell lines, factors known to allosterically regulate GDH1 alter gliogenesis and that SIRT4 and GDH1 overexpression play antagonistic roles in regulating gliogenesis. In addition, an activation mutation of GDH1 accelerates the development of glia from cultured radial glia cells. When in utero electroporation was performed at E16 and at E19, there was no significant change in neuronal migration at E16+4 however there was a migration defect at E19+4 in those cells overexpressing the activation mutation of GDH1. These results implicate a role for GDH1 in the development of astrocytes within the CNS. In the third chapter of this thesis, we show that Sirt1 and HSF1 have important roles in conferring stress resistance and life span extension. Using embryonic neurons and neuroprogenitor cells as models, we show that neuronal differentiation is associated with and facilitated by a decrease in Sirt1 expression, but the maintenance of a basal level of Sirt1 is necessary to prevent apoptotic cell death. A key down-stream effector of Sirt1 for neuroprotection is HSF1, and we show that the activation and expression of HSF1 and induction of HSP70 are decreased in concomitance with neuron differentiation. The results demonstrate the divergent and pivotal role of Sirt1 in regulating the differentiation and survival of neuron. Furthermore, we show that a decreased expression of Sirt1 contributes to the attenuated activation of HSF1 and induction of HSP chaperones in the differentiated neuron.
NotePh.D.
NoteIncludes bibliographical references
NoteIncludes vita
Noteby Daniel Komlos
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3XG9Q63
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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