Neurounion Biomedical Foundation

Santiago, Chile

Neurounion Biomedical Foundation

Santiago, Chile
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Vidal R.L.,University of Chile | Hetz C.,University of Chile | Hetz C.,Harvard University | Hetz C.,Neurounion Biomedical Foundation
Autophagy | Year: 2012

Huntington disease (HD) is caused by an extended polyglutamine [poly(Q)] stretch in the Huntingtin (HTT) protein, and is associated with the accumulation of intracellular protein aggregates, onset of progressive chorea, psychiatric symptoms and dementia. Although the mechanism underlying the pathological effects of mutant HTT (mHTT) remains highly controversial, accumulating evidence suggest that protein-folding stress at the endoplasmic reticulum (ER) may contribute to mHTT-mediated degeneration. ER stress is alleviated by the activation of an adaptive reaction known as the unfolded protein response (UPR), whereas chronic ER stress triggers apoptosis by the same pathway. However, most of the studies linking ER stress with HD in vivo are correlative. UPR signaling is initiated by the activation of at least three distinct stress sensors located at the ER membrane known as ERN1/IRE1a, EIF2AK3/PERK and ATF6. These stress sensors control the expression of specialized transcription factors that modulate the upregulation of a variety of target genes involved in folding, protein quality control, autophagy and protein synthesis. © 2012 Landes Bioscience.

Medinas D.B.,University of Chile | Hetz C.,University of Chile | Hetz C.,Neurounion Biomedical Foundation | Hetz C.,Harvard University
Cell Metabolism | Year: 2013

Altered insulin signaling and neuroinflammation are emerging features of Alzheimer's disease. Lourenco et al. (2013) identify a pathogenic mechanism that is shared between Alzheimer's disease and diabetes and contributes to memory loss through a common molecular event: the control of protein synthesis by PKR and the downstream phosphorylation of eIF2α. © 2013 Elsevier Inc.

Mercado G.,University of Chile | Valdes P.,University of Chile | Hetz C.,University of Chile | Hetz C.,Neurounion Biomedical Foundation | Hetz C.,Harvard University
Trends in Molecular Medicine | Year: 2013

Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta and the accumulation of intracellular inclusions containing α-synuclein (αSyn). Growing evidence from studies in human PD brain, in addition to genetic and toxicological models, indicates that endoplasmic reticulum (ER) stress is a common feature of the disease and contributes to neurodegeneration. Recent reports place ER dysfunction as an early component of PD pathogenesis, and in this article we review the impact of ER stress in PD models and discuss the multiple mechanisms underlying the perturbation of secretory pathway function. Possible therapeutic strategies to mitigate ER stress in the context of PD are also discussed. © 2013 Elsevier Ltd.

Vidal R.L.,Neurounion Biomedical Foundation | Vidal R.L.,University of Chile | Matus S.,Neurounion Biomedical Foundation | Matus S.,University of Chile | And 4 more authors.
Trends in Pharmacological Sciences | Year: 2014

The most prevalent neurodegenerative disorders involve protein misfolding and the aggregation of specific proteins. Autophagy is becoming an attractive target to treat neurodegenerative disorders through the selective degradation of abnormally folded proteins by the lysosomal pathway. However, accumulating evidence indicates that autophagy impairment at different regulatory steps may contribute to the neurodegenerative process. Thus, a complex scenario is emerging where autophagy may play a dual role in neurodegenerative diseases by causing the downstream effect of promoting the degradation of misfolded proteins and an upstream effect where its deregulation perturbs global proteostasis, contributing to disease progression. Challenges in the future development of therapeutic strategies to target the autophagy pathway are discussed. © 2014 Elsevier B.V. All rights reserved.

Mardones P.,University of Chile | Dillin A.,Howard Hughes Medical Institute | Hetz C.,University of Chile | Hetz C.,Neurounion Biomedical Foundation
Cell Metabolism | Year: 2014

Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in hypothalamic neurons are common features of obesity, resulting in leptin and insulin resistance. In this issue, Williams et al. (2014) demonstrate, for the first time, cell-nonautonomous UPR signaling between brain and liver in the context of glucoregulation. © 2014 Elsevier Inc.

Dufey E.,University of Chile | Sepulveda D.,University of Chile | Rojas-Rivera D.,University of Chile | Hetz C.,University of Chile | And 2 more authors.
American Journal of Physiology - Cell Physiology | Year: 2014

Increased demand on the protein folding capacity of the endoplasmic reticulum (ER) engages an adaptive reaction known as the unfolded protein response (UPR). The UPR regulates protein translation and the expression of numerous target genes that contribute to restore ER homeostasis or induce apoptosis of irreversibly damaged cells. UPR signaling is highly regulated and dynamic and integrates information about the type, intensity, and duration of the stress stimuli, thereby determining cell fate. Recent advances highlight novel physiological outcomes of the UPR beyond specialized secretory cells, particularly in innate immunity, metabolism, and cell differentiation. Here we discuss studies on the fine-tuning of the UPR and its physiological role in diverse organs and diseases. © 2014 the American Physiological Society.

Woehlbier U.,University of Chile | Hetz C.,University of Chile | Hetz C.,Harvard University | Hetz C.,Neurounion Biomedical Foundation
Trends in Biochemical Sciences | Year: 2011

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR) through the activation of specialized sensors including inositol-requiring enzyme-1α (IRE1α). IRE1α signals by assembling a dynamic protein platform referred to as the UPRosome, where different modulator and adaptor proteins assemble to regulate the kinetics and amplitude of UPR effector responses. Conversely, chronic ER stress can cause apoptosis. Recent evidence indicates that several apoptosis-related proteins interact with IRE1α, regulating its prosurvival activities and performing a dual function in the regulation of cell death and adaptation to stress. Based on the increasing relevance of ER stress to the occurrence of diverse pathological conditions, strategies to target and modulate the assembly and composition of the UPRosome could have therapeutic benefits for disease intervention. © 2011 Elsevier Ltd.

Rojas-Rivera D.,University of Chile | Hetz C.,University of Chile | Hetz C.,Neurounion Biomedical Foundation
Oncogene | Year: 2014

The control of apoptosis in mammals has been historically associated with the activity of the BCL-2 family of proteins at the mitochondria. In the past years, a novel group of cell death regulators have emerged, known as the Transmembrane BAX Inhibitor-1 Motif-containing (TMBIM) protein family. This group of proteins is composed of at least six highly conserved members expressed in mammals, with homologs in insects, fish, plants, viruses and yeast. Different studies indicate that all TMBIM family members have inhibitory activities in different setting of apoptosis. Here, we overview and integrate possible mechanisms underlying the impact of the TMBIM protein family in the regulation of cell death, which include activities at diverse subcellular compartments, including death receptor regulation, modulation of endoplasmic reticulum (ER) calcium homeostasis, ER stress signaling, autophagy, reactive oxygen species production, among other effects. The possible intersection between the BCL-2 and TMBIM family in the control of cell death is also discussed, in addition to their implication in the progression of cancer.Oncogene advance online publication, 24 February 2014; doi:10.1038/onc.2014.6.

Cornejo V.H.,University of Chile | Hetz C.,University of Chile | Hetz C.,Neurounion Biomedical Foundation | Hetz C.,Harvard University
Seminars in Immunopathology | Year: 2013

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction and accumulation of amyloid-beta (Aβ) peptide, which are responsible for the progressive loss of memory. The mechanisms involved in neuron dysfunction in AD remain poorly understood. Recent evidence implicates the participation of adaptive responses to stress within the endoplasmic reticulum (ER) in the disease process, via a pathway known as the unfolded protein response (UPR). Here, we review the findings suggesting a functional role of ER stress in the etiology of AD. Possible therapeutic strategies to mitigate ER stress in the context of AD are discussed. © 2013 Springer-Verlag Berlin Heidelberg.

Calixto A.,Pontifical Catholic University of Chile | Calixto A.,Major University | Jara J.S.,Pontifical Catholic University of Chile | Court F.A.,Pontifical Catholic University of Chile | Court F.A.,NeuroUnion Biomedical Foundation
PLoS Genetics | Year: 2012

Axonal degeneration is a key event in the pathogenesis of neurodegenerative conditions. We show here that mec-4d triggered axonal degeneration of Caenorhabditis elegans neurons and mammalian axons share mechanistical similarities, as both are rescued by inhibition of calcium increase, mitochondrial dysfunction, and NMNAT overexpression. We then explore whether reactive oxygen species (ROS) participate in axonal degeneration and neuronal demise. C. elegans dauers have enhanced anti-ROS systems, and dauer mec-4d worms are completely protected from axonal degeneration and neuronal loss. Mechanistically, downregulation of the Insulin/IGF-1-like signaling (IIS) pathway protects neurons from degenerating in a DAF-16/FOXO-dependent manner and is related to superoxide dismutase and catalase-increased expression. Caloric restriction and systemic antioxidant treatment, which decrease oxidative damage, protect C. elegans axons from mec-4d-mediated degeneration and delay Wallerian degeneration in mice. In summary, we show that the IIS pathway is essential in maintaining neuronal homeostasis under pro-degenerative stimuli and identify ROS as a key intermediate of neuronal degeneration in vivo. Since axonal degeneration represents an early pathological event in neurodegeneration, our work identifies potential targets for therapeutic intervention in several conditions characterized by axonal loss and functional impairment. © 2012 Calixto et al.

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