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.The 3␤-hydroxysterol-⌬24 reductase (DHCR24) is a broadly expressed oxidoreductase, sharing homologies with a family of flavin adenine dinucleotide-dependent reductases (26). The dhcr24 gene is the human orthologue of the diminuto/dwarf1, initially identified in plants, where it is required for the synthesis of brassinosteroids, a group of plant sterols that are essential for normal growth and development (4,18,23). In mammals, DHCR24 plays an indispensable role in cholesterol biosynthesis, catalyzing the conversion of desmosterol to cholesterol (6, 26, 27). However, DHCR24 was also described in a different context: dhcr24 expression was shown to be downregulated in brain areas affected by Alzheimer's disease (11) and was therefore named seladin-1, the selective Alzheimer's disease indicator 1, suggesting an association of DHCR24/ seladin-1 with the selective vulnerability of neurons in the affected brain areas. Conversely, high levels of DHCR24/seladin-1 exert protective functions, conferring resistance against oxidative stress and protecting cells from apoptotic cell death (2,9,11,16). Endogenous DHCR24/seladin-1 levels are highly up-regulated upon acute oxidative stress (3, 28), while expression declines to very low levels upon chronic exposure (3), suggesting that DHCR24/seladin-1 plays a role in integrating cellular responses to oxidative stress. However, the precise molecular mechanism for this protective effect is not known. Intriguingly, recent findings identified an interaction...

Adaptation of neuronal cells to chronic oxidative stress is associated with altered cholesterol and sphingolipid homeostasis and lysosomal function

“…Desmosterol is a substrate for seladin1, for which we measured reduced mRNA and protein levels in HT22 H2O2 cells. That is consistent with the observed strong accumulation of desmosterol and confirms a recently published study which described a decline of seladin1 expression upon exposure to chronic oxidative stress (Kuehnle et al 2008). Interestingly, in this report, Kuehnle et al found protective effects of both seladin1 over-expression and seladin1 ablation, depending on the duration of the oxidative stress.…”

Desmosterol in Human Nonalcoholic Steatohepatitis

“…37,38 Our gene expression results support the view that desmosterol may have a specific role in activating, e.g., LXR target genes, as compared to cholestenol and lathosterol (Supporting Table 5). Interestingly, the DHCR24 gene function has also been associated with apoptosis and with protective responses to oxidative stress, [39][40][41] all phenomena also important in NASH. Furthermore, HCV infection induces desmosterol accumulation 42 and overexpression of DHCR24 in cell lines.…”

Seladin-1/DHCR24 Is Neuroprotective by Associating EAAT2 Glutamate Transporter to Lipid Rafts in Experimental Stroke

“…1 In addition to the role in cholesterol metabolism, seladin-1/DHCR24 has been reported to play a role in cellular responses against oxidative and oncogenic stress, apoptotic signaling, and inflammation. 1,[5][6][7][8][9] From these series of evidences, it seems reasonable to consider that situations accompanied by a reduction in seladin-1/DHCR24, similarly to that reported in certain Alzheimer's disease brains, …”