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114
induced oxidative stress in neurons. These data were consistent with those findings in yeast mentioned above. But SIRT1 inhibition did not rescue the cells against some other forms of insults, like UV irradiation or a DNA alkylating agent, suggesting that the protective effect could be specific for oxidative stress. To figure out the mechanisms underlying the protection rendered by SIRT1 inhibition we checked the levels of the endogenous antioxidant system including SOD and catalase but could not find any significant change that could explain the protection effect. Then we drew upon the insights from yeast studies showing that both Ras and Sch9 (homologs of mammalian Ras and Akt) are functionally related to Sir2 and exhibit pro-aging activity and sensitize cells to oxidative stress. We first checked if SIRT1 regulates mammalian Ras and Akt signaling. We found that when SIRT1 was inhibited, the activation level of Akt remained unaltered but Ras activity and its downstream ERK1/2 activation were significantly down-regulated. Using inhibitors of MEK1/ERK1/2, we found that inhibition of ERK1/2 could protect neurons against oxidative stress, further verifying that Ras/ERK1/2 at least in part mediate the effects of SIRT1. Further analysis indicated inhibition of SIRT1 or ERK1/2 protected the neurons primarily against necrosis induced by oxidative stress. To see if a similar mechanism occurs in vivo, we measured the oxidative damage in the brains of old mice and found that mice lacking SIRT1 had reduced levels of oxidized proteins as well as oxidized lipids, confirming the results obtained with cultured neurons.
The characterization of the molecular mechanisms underlying SIRT1-mediated effects on Ras/ERK1/2 signaling identified a protein insulin receptor substrate 2 (IRS-2) as a
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 124 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 114 induced oxidative stress in neurons. These data were consistent with those findings in yeast mentioned above. But SIRT1 inhibition did not rescue the cells against some other forms of insults, like UV irradiation or a DNA alkylating agent, suggesting that the protective effect could be specific for oxidative stress. To figure out the mechanisms underlying the protection rendered by SIRT1 inhibition we checked the levels of the endogenous antioxidant system including SOD and catalase but could not find any significant change that could explain the protection effect. Then we drew upon the insights from yeast studies showing that both Ras and Sch9 (homologs of mammalian Ras and Akt) are functionally related to Sir2 and exhibit pro-aging activity and sensitize cells to oxidative stress. We first checked if SIRT1 regulates mammalian Ras and Akt signaling. We found that when SIRT1 was inhibited, the activation level of Akt remained unaltered but Ras activity and its downstream ERK1/2 activation were significantly down-regulated. Using inhibitors of MEK1/ERK1/2, we found that inhibition of ERK1/2 could protect neurons against oxidative stress, further verifying that Ras/ERK1/2 at least in part mediate the effects of SIRT1. Further analysis indicated inhibition of SIRT1 or ERK1/2 protected the neurons primarily against necrosis induced by oxidative stress. To see if a similar mechanism occurs in vivo, we measured the oxidative damage in the brains of old mice and found that mice lacking SIRT1 had reduced levels of oxidized proteins as well as oxidized lipids, confirming the results obtained with cultured neurons. The characterization of the molecular mechanisms underlying SIRT1-mediated effects on Ras/ERK1/2 signaling identified a protein insulin receptor substrate 2 (IRS-2) as a |
