title: Prosurvival effect of DHCR24/Seladin-1 in acute and chronic responses to oxidative stress.
abstract: DHCR24/seladin-1, a crucial enzyme in sterol synthesis, is of lower abundance in brain areas affected by Alzheimer's disease. While high levels of DHCR24/seladin-1 exert antiapoptotic function by conferring resistance against oxidative stress, the molecular mechanism for this protective effect is not fully understood. Here we show that DHCR24/seladin-1 expression is up-regulated in an acute response and down-regulated in a chronic response to oxidative stress. High levels of DHCR24/seladin-1 were associated with elevated cholesterol concentrations and a general increase in cholesterol biosynthesis upon oxidative stress exposure in neuroblastoma SH-SY5Y cells. DHCR24/seladin-1 overexpression conferred resistance to oxidative stress in a cholesterol-dependent manner. Mutating the reductase activity within DHCR24/seladin-1 abolished this protective effect. Conversely, DHCR24/seladin-1 levels diminished upon chronic exposure to oxidative stress. Low levels of DHCR24/seladin-1 were associated with reduced p53 levels, independent of DHCR24 activity and cholesterol concentrations. Additionally, ablation of DHCR24/seladin-1 prevented apoptosis of primary neurons in a p53-dependent manner and reduced the response of critical p53 targets due to deficient stabilization of p53 and therefore elevated p53 ubiquitination and degradation. Our findings reveal a dual capacity of DHCR24/seladin-1, which appears to be involved in two mechanistically independent prosurvival effects, exerting an acute response and a chronic response to oxidative stress.
authors.affiliation: Swiss Academy of Medical Sciences, Petersplatz 13, 4051 Basel, Switzerland. k.kuehnle@samw.ch
authors.forename: Katrin
authors.initials: K
authors.lastname: Kuehnle
authors.forename: Arames
authors.initials: A
authors.lastname: Crameri
authors.forename: Roland E
authors.initials: RE
authors.lastname: Kälin
authors.forename: Paola
authors.initials: P
authors.lastname: Luciani
authors.forename: Susanna
authors.initials: S
authors.lastname: Benvenuti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Peri
authors.forename: Francesca
authors.initials: F
authors.lastname: Ratti
authors.forename: Monica
authors.initials: M
authors.lastname: Rodolfo
authors.forename: Luka
authors.initials: L
authors.lastname: Kulic
authors.forename: Frank L
authors.initials: FL
authors.lastname: Heppner
authors.forename: Roger M
authors.initials: RM
authors.lastname: Nitsch
authors.forename: M Hasan
authors.initials: MH
authors.lastname: Mohajeri
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D002784:Cholesterol; D006861:Hydrogen Peroxide; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human; C499056:Dhcr24 protein, mouse