The response to endoplasmic reticulum stress in neurodegenerative diseases

The capacity of cells to adapt to the changing environment, or to differentiate into specific cell types depends on intracellular signaling mechanisms that coordinate the size and functional capacities of their organelles. Our laboratory studies one of such mechanisms, the Unfolded Protein Response (UPR), that communicates the endoplasmic reticulum (ER) and the cell nucleus. Discovered as an adaptive mechanism that supports cell homeostasis, the UPR senses deficiencies in protein folding within the ER – known as ER stress – to establish a gene expression program that either supports the recovery of cell homeostasis or –when stress is excessive or chronic – leads to cell death.

Specifically, our group is interested in two main questions:

A. Understanding the mechanism by which XBP1 mRNA is delivered to ER stress signaling centers.

A key UPR mechanism is the non-conventional splicing, dedicated to a single mRNA in the cell that encodes the transcription factor XBP1.  Under ER stress, XBP1 mRNA splicing takes place at discrete foci in the cytosolic surface of the ER that are organized by the ER stress transducer/endonuclease IRE1 (Aragon et al. 2009). XBP1 splicing allows the splicing of XBP1s protein, and the activation of a gene expression program to cope with stress. Beyond XBP1 mRNA, IRE1 is able to cleave other mRNA as well as miRNA precursors. However, how are the IRE1 substrates recruited to IRE1? Using genetic, molecular and cell biology approaches we study the molecular mechanism that serves to ensure the efficient UPR splicing under physiological and acute ER stress.

B. The role of UPR signaling in Amyotrophic Lateral Sclerosis and other pathologies.

As a molecular hub that integrates multiple intracellular inputs, the UPR not only supports protein folding homeostasis, but is also intertwined with a wide variety of processes, such as cytokine signaling, metabolism or the maintenance of genome integrity, as evidenced in our recent work on liver UPR (Argemí et al., 2017). Probably UPR signaling is most relevant In the case of neurodegenerative disorders, featured by the loss of protein folding homeostasis and the accumulation of protein aggregates. Under such conditions, the extent and duration of UPR signaling determines the survival of the neuron or its programmed death. In collaboration with the group of Dr. Montserrat Arrasate (CIMA-Neuroscience) we investigate which UPR mechanisms and molecules could serve to enhance neuronal survival in Amyotrophic Lateral Sclerosis, a devastating disorder affecting motor neurons.

Fecha de actualización: Noviembre 2018

"We study the importance of the factor XBP1s in liver pathophysiology and in Parkinson's disease", Dr. Tomás Aragón, Principal Investigator.


Cristina López
Avda. Pío XII, 55
31008 Pamplona

(+34) 948 194 700 Ext. 6021