title: Sirt1 overexpression in neurons promotes neurite outgrowth and cell survival through inhibition of the mTOR signaling.
abstract: The mammalian nicotinamide-adenine dinucleotide (NAD)-dependent deacetylase Sirt1 impacts different processes involved in the maintenance of brain integrity and in the pathogenic pathways associated with several neurodegenerative disorders, including Alzheimer's disease. Here we used human Sirt1 transgenic mice to demonstrate that neuron-specific Sirt1 overexpression promoted neurite outgrowth and improved cell viability under normal and nutrient-limiting conditions in primary culture systems and that Sirt1-overexpressing neurons exhibited higher tolerance to cell death or degeneration induced by amyloid-β1-42 oligomers. Coincidentally, we found that enhanced Sirt1 expression in neurons downregulated the mammalian target of rapamycin (mTOR) protein levels and its phosphorylation without changes in its mRNA levels, which was accompanied by concomitant inhibition of the mTOR downstream signaling activity as revealed by decreased p70S6 kinase (p70S6K) phosphorylation at Thr389. Consistently with this, using a Sirt1 siRNA transfection approach, we observed that reduction of endogenous mouse Sirt1 led to increased levels of mTOR and phosphorylation of itself and p70S6K as well as impaired cell survival and neurite outgrowth in wild-type mouse primary neurons, corroborating a suppressing effect of mTOR by Sirt1. Correspondingly, the mTOR inhibitor rapamycin markedly improved neuronal cell survival in response to nutrient deprivation and significantly enhanced neurite outgrowth in wild-type mouse neurons. The protective effect of rapamycin was extended to neurons even with Sirt1 siRNA knockdown that displayed developmental abnormalities compared with siRNA control-treated cells. Collectively, our findings suggest that Sirt1 may act to promote growth and survival of neurons in the central nervous system via its negative modulation of mTOR signaling.
authors.affiliation: MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, South China Normal University, Guangzhou, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Guo
authors.forename: Lei
authors.initials: L
authors.lastname: Qian
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Alastair
authors.initials: A
authors.lastname: Morrison
authors.forename: Philip
authors.initials: P
authors.lastname: Hayes
authors.forename: Steve
authors.initials: S
authors.lastname: Wilson
authors.forename: Tongsheng
authors.initials: T
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D051379:Mice; D008822:Mice, Transgenic; D016501:Neurites / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D058570:TOR Serine-Threonine Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1