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Efecto del Bexaroteno en ratones transgénicos con esclerosis lateral amiotrófica (ELA) : estudio histológico y molecular

Thesis published in 2020 by Javier Riancho Zarrabeitia
This paper was not found in any repository; the policy of its publisher is unknown or unclear.
This paper was not found in any repository; the policy of its publisher is unknown or unclear.

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Abstract

RESUMEN: La esclerosis lateral amiotrófica (ELA) es una enfermedad neurodegenerativa sin tratamiento efectivo. Actualmente existen indicios de que los retinoides podrían estar implicados en su patogenia. En este trabajo estudiamos los efectos del tratamiento con bexaroteno (Bxt), agonista del receptor X de retinoides (RXR), en el modelo murino de ELA SOD1G93A. El Bxt, a través de la sobre-expresión nuclear del RXR, prolongó la supervivencia y mantuvo la función neuromuscular hasta estadios más avanzados, preservando la citoarquitectura y enlenteciendo la pérdida de motoneuronas, mediante modulación proteostásica y disminución de la astrogliosis. En las motoneuronas de los ratones transgénicos identificamos un mecanismo neuroprotector al estrés de retículo consistente en: i) formación de gránulos de estrés; ii) establecimiento de un dominio perinuclear, enriquecido en retículo endoplásmico granular y pliegues nucleares; y iii) actividad nucleolar preservada, en un intento de preservar la biogénesis de ribosomas para la síntesis de proteínas esenciales para la supervivencia celular. ; ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease without effective treatment. Some authors suggest that retinoids could be implicated on its pathogenesis. In this study we asses if treatment with bexarotene (Bxt), a retinoid X receptor (RXR) agonist, has a beneficial effect in the murine SOD1G93A model of ALS. Treatment with Bxt, trough an enhanced RXR nuclear expression, increased survival and preserved neuromuscular function, ameliorating motor neuron (MN) loss. This drug seems to exert these effects by modulating cellular proteostasis and decreasing astrogliosis. Complementary histological studies in the transgenic mice showed a neuroprotective response in MNs to the stress of the endoplasmic reticulum, mainly based on: i) stress granules formation; ii) establishment of a perinuclear domain of protein synthesis machinery; and iii) preservation of the nucleolar transcription for ribosome biogenesis. This combined response would try to preserve, at least temporarily, the synthesis of those proteins needed for cell survival.