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59
embryonic fibroblasts (MEF) (Luo et al., 2001). In an ALS mouse model SIRT1 rescued neurons (Kim et al., 2007). But SIRT1 can also exacerbate cell death. As described earlier SIRT1 knockout MEFs showed higher replicative life span under chronic sublethal oxidative stress (Chua et al., 2005). SIRT1 also sensitized HEK293 cells to TNF -induced apoptosis (Yeung et al., 2004). Many factors may contribute to the seemingly contradictory effects of SIRT1. First different nutrient, growth or stress signals may be sensed by SIRT1 and integrated into divergent outputs. Secondly, SIRT1’s subcellular localization may also play a role in its regulation of cell death. Some studies suggest that cytoplasm-localized SIRT1 may promote apoptosis (Jin et al., 2007; Zhang, 2007b) while the anti-apoptosis effect may come only from the nuclear-localized SIRT1 (Tanno et al., 2007). Thirdly, SIRT1 has a wide array of targets which may become preferentially (de)activated in different contexts. Deacetylation of p53 and FOXO contributes to the pro-survival effect of SIRT1 (Brunet et al., 2004; Langley et al., 2002; Motta et al., 2004), while NFkB and p19ARF mediate the pro-death effect (Chua et al., 2005; Yeung et al., 2004).
The detection of lower oxidative stress in the brain of SIRT1 knockout mice is consistent with our cell culture data. The reduced production of hydrogen peroxide by mitochondria and major changes in electron transport and leakage in SIRT1 mice recently shown by McBurney and colleagues (Boily et al., 2008b) may explain part of the protective effect observed after SIRT1 inhibition. Yet we cannot conclude that SIRT1 is pro-oxidative damage in all organs in vivo as SIRT1 may play vastly different roles in various organs.
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 69 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 59 embryonic fibroblasts (MEF) (Luo et al., 2001). In an ALS mouse model SIRT1 rescued neurons (Kim et al., 2007). But SIRT1 can also exacerbate cell death. As described earlier SIRT1 knockout MEFs showed higher replicative life span under chronic sublethal oxidative stress (Chua et al., 2005). SIRT1 also sensitized HEK293 cells to TNF -induced apoptosis (Yeung et al., 2004). Many factors may contribute to the seemingly contradictory effects of SIRT1. First different nutrient, growth or stress signals may be sensed by SIRT1 and integrated into divergent outputs. Secondly, SIRT1’s subcellular localization may also play a role in its regulation of cell death. Some studies suggest that cytoplasm-localized SIRT1 may promote apoptosis (Jin et al., 2007; Zhang, 2007b) while the anti-apoptosis effect may come only from the nuclear-localized SIRT1 (Tanno et al., 2007). Thirdly, SIRT1 has a wide array of targets which may become preferentially (de)activated in different contexts. Deacetylation of p53 and FOXO contributes to the pro-survival effect of SIRT1 (Brunet et al., 2004; Langley et al., 2002; Motta et al., 2004), while NFkB and p19ARF mediate the pro-death effect (Chua et al., 2005; Yeung et al., 2004). The detection of lower oxidative stress in the brain of SIRT1 knockout mice is consistent with our cell culture data. The reduced production of hydrogen peroxide by mitochondria and major changes in electron transport and leakage in SIRT1 mice recently shown by McBurney and colleagues (Boily et al., 2008b) may explain part of the protective effect observed after SIRT1 inhibition. Yet we cannot conclude that SIRT1 is pro-oxidative damage in all organs in vivo as SIRT1 may play vastly different roles in various organs. |
