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.
ACKNOWLEDGMENTS
We thank E. Feinstein (Quark Biotech Inc.) for providing the DHCR24-deficient mice.
This work was supported by grants from the Swiss National Science Foundation (3200BO-112616 and 451NF40-111381) (NCCR Neuro), the University of Zurich, the Swiss Academy of Medical Sciences, and the Hermann Klaus, Hartmann Müller, and Novartis Foundations to M.H.M.; by grants from the National Institutes of Health (NINDS R01 NS046006) to F.L.H.; and by EU grants LSHM-CT-2003-503330 (APOPIS) and DFGSFB6027 to R.M.N.