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56
(Jin et al., 2007; Kim et al., 2007; Tanno et al., 2007; Zhang, 2007b). Besides histones, various transcription factors have been identified as substrates for SIRT1. SIRT1-mediated deacetylase activity on these substrates seems to occur in the nucleus.
It has been proposed that SIRT1 plays an anti-aging role in mammals by deacetylating and activating FOXO (Brunet et al., 2004; Kobayashi et al., 2005). Similarly, SIRT1 exhibits antagonistic effects of insulin on PGC-1 in gluconeogenesis (Rodgers et al., 2005). On the other hand, evidence is also accumulating in support of a synergic relationship between Sir2 and insulin/IGF-1. SIRT1 was shown to increase the release of insulin or improve insulin sensitivity (Bordone et al., 2006; Moynihan et al., 2005; Sun et al., 2007). Moreover, SIRT1 lowered the expression of IGF-binding proteins (IGFBP), a secreted inhibitory modulator of IGF function (Yang et al., 2005) and SIRT1 knockout mice have increased expression of IGFBP1 (Lemieux et al., 2005). In agreement with these results, knockdown of liver SIRT1 in mice reduced blood glucose concentration (Rodgers and Puigserver, 2007). In our previous study in S. cerevisiae the deletion of SIR2 increased further the resistance of mutants lacking sch9 (homologous to S6kinase and Akt) to heat shock and oxidative stress but did not increase the resistance of mutants with defects in the Ras/cAMP pathway raising the possibility that Sir2 and Ras function in the same pathway. Although a Ras/cAMP/PKA pathway has not been described in mammalian cells, we provide a mechanism linking SIRT1 activity, the IGF-I/IRS-2/Ras/ERK pathway and stress resistance in mammalian cells. Our results suggest that inhibition of SIRT1 downregulates insulin/IGF-I-dependent activation of ERK1/2 in part
Object Description
| Title | Roles of SIRT1 in neuronal oxidative damage and brain function |
| Author | Li, Ying |
| Author email | lying@usc.edu; yingraceli@yahoo.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2008-09-12 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-10-30 |
| Advisor (committee chair) | Longo, Valter D. |
| Advisor (committee member) |
Baudry, Michel Pike, Christian J. Madigan, Stephen A. |
| Abstract | Aging is a common phenomenon of multiple organisms. In humans aging is frequently accompanied by cognitive decline and occurrence of neurodegenerative diseases which reduce the quality of life and impose financial stress on society. Delaying the aging process, extending life span and decreasing the occurrence of age-related brain function deficit have always been aspirations of human kind. Extensive research has advanced our understanding of the mechanisms underlying aging, among which is the ability of calorie restriction to increase longevity, and the pivotal regulatory roles of insulin/IGF-1 signaling pathway. Some recent studies identified silent information regulator 2 (Sir2; SIRT1 is the mammalian homolog) as a key mediator of the beneficial effects of calorie restriction and this prompted development of SIRT1 activators for human consumption to delay aging and accompanying cognitive decline. However, our laboratory previously showed in yeast that Sir2 can increase stress sensitivity and limit life span extension under certain conditions, calling for more detailed characterization of SIRT1. In the research described in this dissertation I extended this study to the mammalian system and focused on the role of SIRT1 on the health of neurons and brain functions, especially learning and memory.; This dissertation consists of three chapters. In chapter 1 I briefly review some recent progress on aging, oxidative stress, insulin/IGF-1 signaling pathway and learning and memory with emphasis on the involvement of SIRT1 in these processes. In chapter 2 I focused on the role of SIRT1 in oxidative stress in neurons and its mechanisms. I found that SIRT1 inhibition increased resistance to oxidative damage and this effect is partially mediated by a reduction in IGF-I/IRS-2/Ras/ERK1/2 signaling. In chapter 3 I studied the functions of SIRT1 in learning and memory. The experiments showed that deletion of SIRT1 impairs a certain form of synaptic plasticity and reduce performance in several different learning and memory tasks while overexpressing SIRT1 did not substantially affect learning and memory.; Together, my studies reveal that SIRT1 exacerbates neuronal oxidative damage but is essential in learning and memory, indicating that SIRT1 plays multiple roles in aging and brain functions and that caution should be exercised in designing anti-aging or therapeutic approaches that involve targeting SIRT1. |
| Keyword | SIRT1; neurons; brain; oxidative damage; learning and memory |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m1723 |
| Contributing entity | University of Southern California |
| Rights | Li, Ying |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-LI-2405 |
| Archival file | uscthesesreloadpub_Volume44/etd-LI-2405.pdf |
Description
| Title | Page 66 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 56 (Jin et al., 2007; Kim et al., 2007; Tanno et al., 2007; Zhang, 2007b). Besides histones, various transcription factors have been identified as substrates for SIRT1. SIRT1-mediated deacetylase activity on these substrates seems to occur in the nucleus. It has been proposed that SIRT1 plays an anti-aging role in mammals by deacetylating and activating FOXO (Brunet et al., 2004; Kobayashi et al., 2005). Similarly, SIRT1 exhibits antagonistic effects of insulin on PGC-1 in gluconeogenesis (Rodgers et al., 2005). On the other hand, evidence is also accumulating in support of a synergic relationship between Sir2 and insulin/IGF-1. SIRT1 was shown to increase the release of insulin or improve insulin sensitivity (Bordone et al., 2006; Moynihan et al., 2005; Sun et al., 2007). Moreover, SIRT1 lowered the expression of IGF-binding proteins (IGFBP), a secreted inhibitory modulator of IGF function (Yang et al., 2005) and SIRT1 knockout mice have increased expression of IGFBP1 (Lemieux et al., 2005). In agreement with these results, knockdown of liver SIRT1 in mice reduced blood glucose concentration (Rodgers and Puigserver, 2007). In our previous study in S. cerevisiae the deletion of SIR2 increased further the resistance of mutants lacking sch9 (homologous to S6kinase and Akt) to heat shock and oxidative stress but did not increase the resistance of mutants with defects in the Ras/cAMP pathway raising the possibility that Sir2 and Ras function in the same pathway. Although a Ras/cAMP/PKA pathway has not been described in mammalian cells, we provide a mechanism linking SIRT1 activity, the IGF-I/IRS-2/Ras/ERK pathway and stress resistance in mammalian cells. Our results suggest that inhibition of SIRT1 downregulates insulin/IGF-I-dependent activation of ERK1/2 in part |
