The Physiopathological role of nitric oxide in the brain : from translational regulation of the GluN2B subunit to post-translational modifications of albumin in Alzheimer's disease

Ramos Fernández, Eva

The Physiopathological role of nitric oxide in the brain : from translational regulation of the GluN2B subunit to post-translational modifications of albumin in Alzheimer's disease

Document Type

Doctoral thesis
Published Version

Author

Ramos Fernández, Eva

Director

Muñoz López, Francisco José

Publication Date

2013-01-16

Pages

225 p.

Citation

Ramos Fernández, E. The Physiopathological role of nitric oxide in the brain : from translational regulation of the GluN2B subunit to post-translational modifications of albumin in Alzheimer's disease. Universitat Pompeu Fabra; 2013. handle: http://hdl.handle.net/10803/129925

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

Nitric oxide (NO) is a molecule that has pleiotropic effects in brain and vascular system. Physiologically, NO induces the translation of the GluN2B subunit of N-methyl Daspartate receptor (NMDARc) by derepressing it 5’untranslated region (5’UTR) effect. This pathway is due to the activation of the heme regulated eIF2α (HRI) kinase and prevents an excess of GluN2B levels, especially at the extrasynaptic areas, where it can trigger excitotoxicity. Pathologically, NO in a pro-oxidant environment such as in Alzheimer’s Disease (AD) reacts with superoxide anion producing peroxynitrite, which can nitrotyrosinates proteins. There are other concomitant oxidative processes that affect AD patient like protein glycation. Therefore the albumin, the most abundant plasmatic protein, in AD patients is more nitrotyrosinated and glycated, which affects its structure. Modified albumin has a reduced ability as an osmolarity buffer and it is hardly uptaken by hepatoma cells. Moreover, modified albumin binds more Aβ, contributing to maintain higher amount of amyloid in brain and plasma.
El óxido nítrico (NO) es una molécula con efectos pleyotrópicos en cerebro y sistema vascular. Fisiológicamente, induce la traducción de la subunidad GluN2B del N-methyl D-aspartate receptor (NMDARc) al revertir la represión de su 5’untranslated region (5’UTR). Este efecto se debe a la activación de la heme regulated eIF2α kinase (HRI) y previene el exceso de GluN2B, especialmente en regiones extrasinápticas, donde desencadena excitotoxicidad. Patológicamente, el NO en un ambiente pro-oxidatvio como el dado en la enfermedad de Alzheimer (AD) reacciona con el anión superóxido produciendo peroxinitrito, y causando entre otros efectos la nitrotirosinación de proteínas. Simultaneamente, las proteínas de pacientes con AD padecen otros procesos oxidativos como la glicación. Por tanto, la albúmina, la proteína plasmática más abundante, en estos pacientes está más nitrotirosinada y glicada, afectando su estructura. La albúmina modificada presenta menos capacidad para tamponar la osmolaridad y apenas es digerida por las células de hepatoma. Además, une más Aβ, contribuyendo a mantener más alta la carga amiloidogénica en cerebro y plasma.

Keywords

GluN2B subunit, 5’ UTR, Albumin, Alzheimer’s disease, Nitrotyrosination, Glycation, Oxidative stress, Amyloid‐β‐peptide, Subunidad GluN2B, Albúmina, Enfermedad de Alzheimer, Nitrotirosinación, Glicación, Estrés oxidativo, Péptido β amiloide