3 β-Hydroxysteroid-Δ 24 Reductase (DHCR24) Protects Neuronal Cells from Apoptotic Cell Death Induced by Endoplasmic Reticulum (ER) Stress

Abstract

3β-Hydroxysteroid-Δ24 reductase (DHCR24) is an endoplasmic reticulum (ER)-localized multifunctional enzyme that possesses anti-apoptotic and cholesterol-synthesizing activities. Accumulating evidence suggests that ER stress is involved in the pathogenesis of neurodegenerative disease. In this study, we investigated whether DHCR24 may function as a neuroprotective protein under ER stress. Neuroblastoma N2A cells were infected with adenovirus expressing myc-tagged DHCR24 (Ad-DHCR24) or lacZ (Ad-lacZ, serving as a control) and subjected to ER-stress, induced with Tunicamycin (TM). Cells infected with Ad-DHCR24-myc were resistant to TM-induced apoptosis, and showed weaker level of caspase-12 activity. These cells also exhibited lower levels of Bip and CHOP proteins than Ad-LacZ-infected cells. Moreover, a stronger and rapid activation of PERK, and a prolonged activation of JNK and p38 were observed in Ad-LacZ–infected cells. The generation of intracellular reactive oxygen species from ER stress was also diminished by the overexpression of DHCR24. Additionally, intracellular cholesterol level was also elevated in the Ad-DHCR24-infected cells, accompanied by a well-organized formation of caveolae (cholesterol-rich microdomain) on the plasma membrane, and improved colocalization of caveolin-1 and insulin-like growth factor 1 receptor. These results demonstrated for the first time that DHCR24 could protect neuronal cells from apoptosis induced by ER stress.

Developmental exposure to ethanol increases the neuronal vulnerability to oxygen–glucose deprivation in cerebellar granule cell cultures

“…A close inspection of the GO category "oxidation-reduction process" revealed an ethanol-induced up-regulation of Dhcr24 shown to exert a neuroprotective effect against reactive oxygen species resulted from endoplasmic reticulum stress (Lu et al, 2014). The down-regulation of Cp, an important antioxidant molecule, is in accordance to previous studies on hippocampi after chronic ethanol exposure (Saito et al, 2002).…”

“…1 and 3A). Overexpression of Dhcr24 was shown to inhibit apoptotic cell signaling (Lu et al, 2014), hence it seems reasonable to assume that the observed upregulation of Dhcr24 is a counterbalance that prevents the commitment on the activated apoptotic pathway in CGCs.…”

Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann–Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis*

“…DHCR24 protein is of particular interest and potentially relevant in the context of NPC disease. It is an ER-localized multifunctional enzyme and has shown to protect neuronal cells from apoptosis induced by ER stress (27). Interestingly, apoptosis is one of the enriched GO terms in the analysis of DEPs data set with Ontologizer ( Fig.…”

“…DHCR24 (also known as Seladin-1) is involved in the final step of cholesterol biosynthesis, catalyzing the conversion of desmosterol to cholesterol by saturating the C-24,25 double bond in its sidechain (28). DHCR24 suppresses the excess generation of intracellular ROS from ER stress and functions as an antiapoptotic and neuroprotective protein (27). Therefore, we examined the effect of various classes of drugs that are currently being tested for efficacy in NPC treatment, such as cyclodextrins (HPCD/M␤CD), HDACIs (Cl-994, SAHA, VPA), antioxidant NAC, and an oxysterol derivative pharmacological chaperone (mo56HC) on the expression level of SOD2 and DHCR24 in NPC1 I1061T cells.…”

The GARD platform for potency assessment of skin sensitizing chemicals_suppl

“…For each new model, we repeated the complete process of variable selection in purine biosynthesis (Lane and Fan, 2015;Li et al, 2007), and TMEM97 (part of GPS) is a regulator of cholesterol levels (Bartz et al, 2009), which is further described to be involved in cell cycle regulation, cell migration and invasion in a glioma cell model according to RNA interference experiments (Qiu et al, 2015). DHCR24 (another GPS transcript) represents a multifunctional enzyme localized to the endoplasmic reticulum (ER) that catalyzes the final step in cholesterol-synthesis (Waterham et al, 2001) but also possesses anti-apoptotic activity as, for example, shown for neuronal cells under ER stress (Lu et al, 2014). PLK1, a kinase, has been shown to be phosphorylated in response to TLR activation and results from RNA interference suggested that PLK1 signaling was involved in the TLR-induced inflammatory response (Hu et al, 2013).…”