title: 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.
authors.affiliation: Endocrine Unit, Department of Clinical Physiopathology, Center for Research, Transfer and High Education on Chronic Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies, University of Florence, Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Luciani
authors.forename: Cristiana
authors.initials: C
authors.lastname: Deledda
authors.forename: Fabiana
authors.initials: F
authors.lastname: Rosati
authors.forename: Susanna
authors.initials: S
authors.lastname: Benvenuti
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cellai
authors.forename: Francesca
authors.initials: F
authors.lastname: Dichiara
authors.forename: Matteo
authors.initials: M
authors.lastname: Morello
authors.forename: Gabriella Barbara
authors.initials: GB
authors.lastname: Vannelli
authors.forename: Giovanna
authors.initials: G
authors.lastname: Danza
authors.forename: Mario
authors.initials: M
authors.lastname: Serio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Peri
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D019610:Cytoprotection / Q000187:drug effects* / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D004958:Estradiol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human