title: ApoER2 processing by presenilin-1 modulates reelin expression.
abstract: The reelin signaling protein and its downstream components have been associated with synaptic plasticity and neurotransmission. The reelin signaling pathway begins with the binding of reelin to the transmembrane lipoprotein receptor apolipoprotein E receptor 2 (ApoER2), which in turns induces the sequential cleavage of ApoER2 by the sequential action of α- and γ-secretases. Using conditional-knockout mice of the catalytic component of the γ-secretase complex, presenilin 1 (PS1), we demonstrated increased brain ApoER2 and reelin protein and transcript levels, with no changes in the number of reelin-positive cells. Using the human SH-SY5Y neuroblastoma cell line, we showed that ApoER2 processing occurs in the presence of PS1, producing an intracellular ApoER2 C-terminal fragment. In addition, the pharmacologic inhibition of γ-secretase in SH-SY5Y cells led to increased reelin levels. Overexpression of ApoER2 decreased reelin mRNA levels in these cells. A luciferase reporter gene assay and nuclear fractionation confirmed that increased amounts of intracellular fragment of ApoER2 suppressed reelin expression at a transcriptional level. Chromatin immunoprecipitation experiments corroborated that the intracellular fragment of ApoER2 bound to the RELN promoter region. Our study suggests that PS1/γ-secretase-dependent processing of the reelin receptor ApoER2 inhibits reelin expression and may regulate its signaling.
authors.affiliation: 1Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Av. Ramón y Cajal s/n, E-03550 Sant Joan d'Alacant, Spain. j.saez@umh.es.
authors.forename: Valeria
authors.initials: V
authors.lastname: Balmaceda
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Cuchillo-Ibáñez
authors.forename: Lluis
authors.initials: L
authors.lastname: Pujadas
authors.forename: María-Salud
authors.initials: MS
authors.lastname: García-Ayllón
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Saura
authors.forename: Johannes
authors.initials: J
authors.lastname: Nimpf
authors.forename: Eduardo
authors.initials: E
authors.lastname: Soriano
authors.forename: Javier
authors.initials: J
authors.lastname: Sáez-Valero
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D000091042:Reelin Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D004151:Dipeptides; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; D008156:Luciferases; D053829:Amyloid Precursor Protein Secretases; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases
keywords: Alzheimer's disease; Reelin; transcription