ApoER2 processing by presenilin-1 modulates reelin expression


Por: Balmaceda V, Cuchillo-Ibáñez I, Pujadas L, García-Ayllón MS, Saura CA, Nimpf J, Soriano E and Saez J

Publicada: 1 abr 2014
Resumen:
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 alpha- and gamma-secretases. Using conditional-knockout mice of the catalytic component of the gamma-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 gamma-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/gamma-secretase-dependent processing of the reelin receptor ApoER2 inhibits reelin expression and may regulate its signaling.-Balmaceda, V., Cuchillo-Ibanez, I., Pujadas, L., Garcia-Ayllon, M.-S., Saura, C. A., Nimpf, J., Soriano, E., Saez-Valero, J. ApoER2 processing by presenilin-1 modulates reelin expression.

Filiaciones:
Balmaceda V:
 1Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Av. Ramón y Cajal s/n, E-03550 Sant Joan d'Alacant, Spain.
ISSN: 15306860





FASEB JOURNAL
Editorial
Federation of American Societies for Experimental Biology, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA, Estados Unidos America
Tipo de documento: Article
Volumen: 28 Número: 4
Páginas: 1543-1554
WOS Id: 000335344300004
ID de PubMed: 24344333
imagen Green Submitted

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