Alterations in organelle function have devastating consequences for the proper function of the cell. Stress injuries initiate multiple signaling responses, either to adapt to the new conditions or to activate specific cell death pathways, if a critical threshold of damage has been reached. Our laboratory is committed to the study of cellular strategies involved in adaptation to chronic organelle damage, which are linked to several neurological disorders. The endoplasmic reticulum (ER) has important cellular functions and is well known for its role as a sophisticated machinery for protein folding and secretion. Alterations on ER function lead to the accumulation of unfolded proteins in its lumen, a cellular condition termed “ER stress”. ER stress triggers a complex adaptive reaction known as the “Unfolded Protein Response” (UPR), which aims to restore this organelle’s homeostasis. Sustained ER stress ultimately promotes apoptosis, where the members of the BCL-2 family of proteins are essential in the initiation of cell death. Nevertheless, the mechanisms that control the transition from an adaptive state to cell death processes remain unknown.
ER stress and diseases - Chronic ER stress is associated with neurodegenerative conditions linked to the accumulation in the brain of abnormal misfolded proteins. Such diseases include Prion diseases, Parkinson, Alzheimer, ALS, and many others. The contribution of the IRE1α pathway to the disease process, however, remains unknown. Our laboratory is particularly committed to investigate stress responses linked to irreversible ER damage and to understand how this pathway influences pathological conditions affecting the nervous system. Our research is focused on studying different aspects of UPR function and addresses two central questions:.
1. To assess the molecular mechanism involved in the regulation of the UPR.
2. Define the contribution of the ER stress pathway to pathological conditions affecting the nervous system.
Therefore, we are committed in first place to generate mechanistic insights about IRE1α signaling and, in second place, to apply this investigation to the study of neurodegenerative diseases linked to ER dysfunction. Some of the diseases that we are currently investigating include Prion-related disorders, Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis and spinal cord injury. In addition, we are currently developing therapeutic strategies to cure this disease using animal models and gene therapy strategies using interfering RNA and genetically modified viral vectors.