Time filter

Source Type

Santiago, Chile

Nivon M.,University of Lyon | Nivon M.,French Institute of Health and Medical Research | Fort L.,University of Lyon | Fort L.,French Institute of Health and Medical Research | And 19 more authors.
Molecular Biology of the Cell

During cell life, proteins often misfold, depending on particular mutations or environmental changes, which may lead to protein aggregates that are toxic for the cell. Such protein aggregates are the root cause of numerous diseases called "protein conformational diseases," such as myofibrillar myopathy and familial amyotrophic lateral sclerosis. To fight against aggregates, cells are equipped with protein quality control mechanisms. Here we report that NFκB transcription factor is activated by misincorporation of amino acid analogues into proteins, inhibition of proteasomal activity, expression of the R120G mutated form of HspB5 (associated with myofibrillar myopathy), or expression of the G985R and G93A mutated forms of superoxide dismutase 1 (linked to familial amyotrophic lateral sclerosis). This noncanonical stimulation of NFκB triggers the up-regulation of BAG3 and HspB8 expression, two activators of selective autophagy, which relocalize to protein aggregates. Then NFκB-dependent autophagy allows the clearance of protein aggregates. Thus NFκB appears as a central and major regulator of protein aggregate clearance by modulating autophagic activity. In this context, the pharmacological stimulation of this quality control pathway might represent a valuable strategy for therapies against protein conformational diseases. © 2016 Nivon et al. Source

Mardones P.,University of Chile | Mardones P.,Center for Geroscience | Rubinsztein D.C.,University of Cambridge | Hetz C.,University of Chile | And 2 more authors.
Science Signaling

Although vertebrates cannot synthesize the natural disaccharide trehalose, exogenous administration of trehalose to mammalian cells may be beneficial for protein misfolding disorders. In this issue, DeBosch et al. show that trehalose may also be useful in treating nonalcoholic fatty liver disease and identify inhibition of cellular glucose import through SLC2A (also known as GLUT) transporters as a mechanism by which trehalose stimulates autophagy through the adenosine monophosphate- activated protein kinase (AMPK). © 2016 by the American Association for the Advancement of Science. Source

Valenzuela V.,University of Chile | Valenzuela V.,Center for Geroscience | Martinez G.,University of Chile | Martinez G.,Center for Geroscience | And 5 more authors.
Brain Research

Gene therapy based on the use of Adeno-associated viruses (AAVs) is emerging as a safe and stable strategy to target molecular pathways involved in a variety of brain diseases. Endoplasmic reticulum (ER) stress is proposed as a transversal feature of most animal models and clinical samples from patients affected with neurodegenerative diseases. Manipulation of the unfolded protein response (UPR), a major homeostatic reaction under ER stress conditions, had proved beneficial in diverse models of neurodegeneration. Although increasing number of drugs are available to target ER stress, the use of small molecules to treat chronic brain diseases is challenging because of poor blood brain barrier permeability and undesirable side effects due to the role of the UPR in the physiology of peripheral organs. Gene therapy is currently considered a possible future alternative to circumvent these problems by the delivery of therapeutic agents to selective regions and cell types of the nervous system. Here we discuss current efforts to design gene therapy strategies to alleviate ER stress on a disease context. . This article is part of a Special Issue entitled SI:ER stress. © 2016 Elsevier B.V. Source

Urra H.,University of Chile | Urra H.,Center for Geroscience | Dufey E.,University of Chile | Dufey E.,Center for Geroscience | And 6 more authors.
Trends in Cancer

Tumor cells are often exposed to intrinsic and external factors that alter protein homeostasis, thus producing endoplasmic reticulum (ER) stress. To cope with this, cells evoke an adaptive mechanism to restore ER proteostasis known as the unfolded protein response (UPR). The three main UPR signaling branches initiated by IRE1α, PERK, and ATF6 are crucial for tumor growth and aggressiveness as well as for microenvironment remodeling or resistance to treatment. We provide a comprehensive overview of the contribution of the UPR to cancer biology and the acquisition of malignant characteristics, thus highlighting novel aspects including inflammation, invasion and metastasis, genome instability, resistance to chemo/radiotherapy, and angiogenesis. The therapeutic potential of targeting ER stress signaling in cancer is also discussed. Trends Highly proliferative tumors are exposed to several intrinsic and extrinsic factors that induce adaptation to stress conditions. ER stress is a common feature of different types of blood and solid cancers. Adaptation to ER stress is achieved by the activation of the UPR. The UPR is involved in the acquisition of several malignant characteristics that allow tumor growth. ER stress signaling also occurs in stromal cells such as endothelial, macrophage, and dendritic cells, suggesting a novel concept of 'transmissible ER stress'. Although the acquisition of tumor characteristics is driven by UPR signaling events, some of these features are independent of ER stress, as observed in angiogenesis and tumor-promoting inflammation. Several specific small molecules that inhibit UPR stress sensors (IRE1α and PERK) have beneficial effects in multiple myeloma and pancreatic cancer. © 2016 Elsevier Inc. Source

Garcia-Huerta P.,University of Chile | Garcia-Huerta P.,Center for Geroscience | Troncoso-Escudero P.,University of Chile | Troncoso-Escudero P.,Center for Geroscience | And 7 more authors.
Brain Research

One of the salient features of most neurodegenerative diseases is the aggregation of specific proteins in the brain. This proteostasis imbalance is proposed as a key event triggering the neurodegenerative cascade. The unfolded protein response (UPR) and autophagy pathways are emerging as critical processes implicated in handling disease-related misfolded proteins. However, in some conditions, perturbations in the buffering capacity of the proteostasis network may be part of the etiology of the disease. Thus, pharmacological or gene therapy strategies to enhance autophagy or UPR responses are becoming an attractive target for disease intervention. Here, we discuss current evidence depicting the complex involvement of autophagy and ER stress in brain diseases. Novel pathways to modulate protein misfolding are discussed including the relation between aging and growth factor signaling. This article is part of a Special Issue entitled SI:Autophagy. © 2016 Elsevier B.V. Source

Discover hidden collaborations