Endoplasmic Reticulum Stress Response in Neurodegenerative Diseases

"We studied the relevance of XBP1s factor in liver pathophysiology and Parkinson's disease."


The ability of cells to adapt to changes in their environment, or to transform into specific cell types, depends on intracellular signaling mechanisms that coordinate the size and functional capacity of their organelles.

The Endoplasmic Reticulum Stress Response in Neurodegenerative Diseases Research Group studies one of these mechanisms, the Unfolded Protein Response (UPR), which communicates the endoplasmic reticulum (ER) with the cell nucleus.

Discovered as an adaptive mechanism that promotes cellular homeostasis, the UPR detects defects in ER protein folding - a situation commonly referred to as ER stress - to establish a gene expression program that facilitates the recovery of homeostasis or, when the stress is excessive or chronic, leads to cell death.

Dr. Tomás Aragón Amonarriz


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Objectives of the Research Group

Understanding the mechanism by which XBP1 messenger RNA is transported to ER stress response centers

A key mechanism of the UPR is mediated by unconventional processing dedicated to a unique messenger RNA in the cell, which encodes the transcription factor XBP1. Under conditions of ER stress, the XBP1 mRNA is processed in discrete ER foci, organized by the ER stress sensor IRE1 (Aragon et al. 2009). Such splicing allows the synthesis of XBP1s protein and activation of a stress-relieving gene expression program. In addition to the XBP1 mRNA, IRE1 cleaves other mRNAs as well as precursors of microRNAs. But how are these RNAs transported to stress response foci? Using genetic, molecular and cellular biology approaches, we study the mechanism that facilitates the efficient processing of RNAs under both physiological and acute stress conditions.

Studying the role of the UPR in Amyotrophic Lateral Sclerosis and other pathologies

Recent studies have shown that the UPR is actually an intracellular information node that integrates multiple inputs within the cell. Through this interconnection with other processes, the UPR participates in actions such as maintenance of genome integrity, metabolism or response to cytokines as shown by our recent studies on the role of XBP1 in liver regeneration (Argemí et al., 2017). But the importance of the UPR is particularly revealed in the case of neurodegenerative diseases, characterized by deficiencies in protein folding, and in the accumulation of protein aggregates. Under these conditions, the UPR is critically involved in determining whether, in response to stress, the neuron survives or dies. In collaboration with Dr. Montserrat Arrasate's group (CIMA-Neurosciences) we investigated which components of the UPR contribute to improve neuronal survival in Amyotrophic Lateral Sclerosis, a very severe disease caused by the death of motor neurons.

Scientific Activity of the Endoplasmic reticulum stress response in neurodegenerative diseases Research Group