Seladin-1 Is a Fundamental Mediator of the Neuroprotective Effects of Estrogen in Human Neuroblast Long-Term Cell Cultures

Abstract

Estrogen exerts neuroprotective effects and reduces beta-amyloid accumulation in models of Alzheimer's disease (AD). A few years ago, a new neuroprotective gene, i.e. seladin-1 (for selective AD indicator-1), was identified and found to be down-regulated in AD vulnerable brain regions. Seladin-1 inhibits the activation of caspase-3, a key modulator of apoptosis. In addition, it has been demonstrated that the seladin-1 gene encodes 3beta-hydroxysterol Delta24-reductase, which catalyzes the synthesis of cholesterol from desmosterol. We have demonstrated previously that in fetal neuroepithelial cells, 17beta-estradiol (17betaE2), raloxifene, and tamoxifen exert neuroprotective effects and increase the expression of seladin-1. The aim of the present study was to elucidate whether seladin-1 is directly involved in estrogen-mediated neuroprotection. Using the small interfering RNA methodology, significantly reduced levels of seladin-1 mRNA and protein were obtained in fetal neuroepithelial cells. Seladin-1 silencing determined the loss of the protective effect of 17betaE2 against beta-amyloid and oxidative stress toxicity and caspase-3 activation. A computer-assisted analysis revealed the presence of half-palindromic estrogen responsive elements upstream from the coding region of the seladin-1 gene. A 1490-bp region was cloned in a luciferase reporter vector, which was transiently cotransfected with the estrogen receptor alpha in Chinese hamster ovarian cells. The exposure to 17betaE2, raloxifene, tamoxifen, and the soy isoflavones genistein and zearalenone increased luciferase activity, thus suggesting a functional role for the half-estrogen responsive elements of the seladin-1 gene. Our data provide for the first time a direct demonstration that seladin-1 may be considered a fundamental mediator of the neuroprotective effects of estrogen.

Signaling regulates activity of DHCR24, the final enzyme in cholesterol synthesis

“…Samples (1 l) were injected via a heated (290°C) splitless inlet into an Rxi-5Sil mass spectrometer with Integra-Guard, 30 m × 0. 25 antibody, with the bottom band being the nonphosphorylated ERK1/2, as confi rmed with phosphorylated ERK1/2 (pERK1/2) antibody ( Fig. 1C , left panel).…”

“…mRNA levels were determined by quantitative real-time reverse transcription PCR (qRT-PCR) using the Corbett Rotorgene 3000 (Corbett Life nuclear factor Y sites in the human DHCR24 promoter that mediate this regulation ( 23 ). Moreover, DHCR24 is regulated at the transcriptional level by sex steroids ( 24,25 ), adrenocorticotropic hormone ( 26 ), thyroid hormone ( 27 ), and xenobiotics ( 28 ). Epigenetic factors such as methylation and acetylation also regulate DHCR24 expression ( 29 ).…”

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, …”

Neuroprotection in Perimenopausal Women

“…β-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. The Italian studies from Florence have demonstrated that estradiol is restoring in menopause the neuroprotective gene, seladin-1 (for SELective Alzheimer's Disease INdicator-1), or the gene DHCR24, which is downregulated in AD [74]. This gene inhibits the activation of caspase-3, a key modulator of apoptosis, and the gene encodes 3β-hydroxysterol, which catalyzes the conversion of desmosterol into cholesterol, and an appropriate amount of membrane cholesterol plays a pivotal role to protect nerve cells against Aβ toxicity and counteracts the synthesis of Aβ in AD [75,76].…”