Prosurvival effect of DHCR24/Seladin-1 in acute and chronic responses to oxidative stress.
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.
Kuehnle
Katrin
K
Swiss Academy of Medical Sciences, Petersplatz 13, 4051 Basel, Switzerland. k.kuehnle@samw.ch
Crameri
Arames
A
Kälin
Roland E
RE
Luciani
Paola
P
Benvenuti
Susanna
S
Peri
Alessandro
A
Ratti
Francesca
F
Rodolfo
Monica
M
Kulic
Luka
L
Heppner
Frank L
FL
Nitsch
Roger M
RM
Mohajeri
M Hasan
MH
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
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