Center for Geroscience

Santiago, Chile

Center for Geroscience

Santiago, Chile

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Obacz J.,University of Rennes 1 | Avril T.,University of Rennes 1 | Le Reste P.-J.,University of Rennes 1 | Le Reste P.-J.,University Hospital Pontchaillou | And 8 more authors.
Science Signaling | Year: 2017

Cellular stress induced by the accumulation of misfolded proteins at the endoplasmic reticulum (ER) is a central feature of secretory cells and is observed in many tissues in various diseases, including cancer, diabetes, obesity, and neurodegenerative disorders. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the cytosol and nucleus to restore proteostasis. In the past decade, ER stress has emerged as a major pathway in remodeling gene expression programs that either prevent transformation or provide selective advantage in cancer cells. Controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, UPR signaling is a highly regulated process that leads to an integrated reprogramming of the cell. In this Review, we provide an overview of the regulatory mechanisms underlying UPR signaling and how this pathway modulates cancer progression, particularly the aggressiveness and chemotherapeutic resistance exhibited by glioblastoma, a form of brain cancer. We also discuss the emerging cross-talk between the UPR and related metabolic processes to ensure maintenance of proteostasis, and we highlight possible therapeutic opportunities for targeting the pathway with small molecules. © 2017 The Authors, some rights reserved.

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 | Year: 2016

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.

Villarroel-Campos D.,University of Chile | Villarroel-Campos D.,Center for Geroscience | Bronfman F.C.,University of Santiago de Chile | Gonzalez-Billault C.,University of Chile | Gonzalez-Billault C.,Center for Geroscience
Cytoskeleton | Year: 2016

Neurons are highly polarized cells that contain specialized subcellular domains involved in information transmission in the nervous system. Specifically, the somatodendritic compartment receives neuronal inputs while the axons convey information through the synapse. The establishment of asymmetric domains requires a specific delivery of components, including organelles, proteins, and membrane. The Rab family of small GTPases plays an essential role in membrane trafficking. Signaling cascades triggered by extrinsic and intrinsic factors tightly regulate Rab functions in cells, with Rab protein activation depending on GDP/GTP binding to establish a binary mode of action. This review summarizes the contributions of several Rab family members involved in trans-Golgi, early/late endosomes, and recycling endosomes during neurite development and axonal outgrowth. The regulation of some Rabs by guanine exchanging factors and GTPase activating proteins will also be addressed. Finally, discussion will be provided on how specific effector-mediated Rab activation modifies several molecules essential to neuronal differentiation. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

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 | Year: 2016

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.

Ahumada-Galleguillos P.,University of Chile | Ahumada-Galleguillos P.,Biomedical Neuroscience Institute | Ahumada-Galleguillos P.,Center for Geroscience | Lemus C.G.,University of Chile | And 10 more authors.
Brain Structure and Function | Year: 2016

Brain asymmetry is a conserved feature in vertebrates. The dorsal diencephalic habenular complex shows conspicuous structural and functional asymmetries in a wide range of species, yet it is unclear if this condition is also present in humans. Addressing this possibility becomes relevant in light of recent findings presenting the habenula as a novel target for therapeutic intervention of affective disorders through deep brain stimulation. Here we performed volumetric analyses in postmortem diencephalic samples of male and female individuals, and report for the first time, the presence of directional asymmetries in the volume of the human habenula. The habenular volume is larger on the left side in both genders, a feature that can be explained by an enlargement of the left lateral habenula compared to the right counterpart. In contrast, the volume of the medial habenula shows no left–right directional bias in either gender. It is remarkable that asymmetries involve the lateral habenula, which in humans is particularly enlarged compared to other vertebrates and plays relevant roles in aversive processing and aversively motivated learning. Our findings of structural asymmetries in the human habenula are consistent with recent observations of lateral bias in activation, metabolism and damage of the human habenula, highlighting a potential role of habenular laterality in contexts of health and illness. © 2016 Springer-Verlag Berlin Heidelberg

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 | Year: 2016

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.

Bodaleo F.J.,University of Chile | Bodaleo F.J.,Center for Geroscience | Gonzalez-Billault C.,University of Chile | Gonzalez-Billault C.,Center for Geroscience | Gonzalez-Billault C.,The Buck Institute for Research on Aging
Frontiers in Molecular Neuroscience | Year: 2016

The capacity of the nervous system to generate neuronal networks relies on the establishment and maintenance of synaptic contacts. Synapses are composed of functionally different presynaptic and postsynaptic compartments. An appropriate synaptic architecture is required to provide the structural basis that supports synaptic transmission, a process involving changes in cytoskeletal dynamics. Actin microfilaments are the main cytoskeletal components present at both presynaptic and postsynaptic terminals in glutamatergic synapses. However, in the last few years it has been demonstrated that microtubules (MTs) transiently invade dendritic spines, promoting their maturation. Nevertheless, the presence and functions of MTs at the presynaptic site are still a matter of debate. Early electron microscopy (EM) studies revealed that MTs are present in the presynaptic terminals of the central nervous system (CNS) where they interact with synaptic vesicles (SVs) and reach the active zone. These observations have been reproduced by several EM protocols; however, there is empirical heterogeneity in detecting presynaptic MTs, since they appear to be both labile and unstable. Moreover, increasing evidence derived from studies in the fruit fly neuromuscular junction proposes different roles for MTs in regulating presynaptic function in physiological and pathological conditions. In this review, we summarize the main findings that support the presence and roles of MTs at presynaptic terminals, integrating descriptive and biochemical analyses, and studies performed in invertebrate genetic models. © 2016 Bodaleo and Gonzalez-Billault.

Court F.A.,Major University | Court F.A.,Center for Geroscience | Court F.A.,University of Santiago de Chile | Alvarez J.,University of Santiago de Chile
Advances in Experimental Medicine and Biology | Year: 2016

Here we propose a model of a peripheral axon with a great deal of autonomy from its cell body-the autonomous axon-but with a substantial dependence on its ensheathing Schwann cell (SC), the axon-SC unit. We review evidence in several fields and show that (i) axons can extend sprouts and grow without the concurrence of the cell body, but regulated by SCs; (ii) axons synthesize their proteins assisted by SCs that supply them with ribosomes and, probably, with mRNAs by way of exosomes; (iii) the molecular organization of the axoplasm, i.e., its phenotype, is regulated by the SC, as illustrated by the axonal microtubular content, which is down-regulated by the SC; and (iv) the axon has a program for self-destruction that is boosted by the SC. The main novelty of this model axon-SC unit is that it breaks with the notion that all proteins of the nerve cell are specified by its own nucleus. The notion of a collaborative specification of the axoplasm by more than one nucleus, which we present here, opens a new dimension in the understanding of the nervous system in health and disease and is also a frame of reference to understand other tissues or cell associations. © Springer International Publishing Switzerland 2016.

Uribe-Arias A.,University of Antioquia | Posada-Duque R.A.,University of Antioquia | Gonzalez-Billault C.,University of Chile | Gonzalez-Billault C.,Center for Geroscience | And 3 more authors.
Journal of Neurochemistry | Year: 2016

Cyclin-dependent kinase 5 (CDK5) plays important roles in synaptic function. Its unregulated over-activation has been, however, associated with neurodegeneration in Alzheimer's disease. Our previous studies revealed that CDK5 silencing ameliorates tauopathy and spatial memory impairment in the 3xTgAD mouse model. However, how CDK5 targeting affects synaptic adhesion proteins, such as those involved in the cadherin/catenin system, during learning and memory processes is not completely understood. In this study, we detected reduced expression of p120 catenin (p120 ctn), N-cadherin, and β-catenin in the brain of human Alzheimer's disease patients, in addition to a reduced PSD95 and GluN2B protein levels in a 3xTgAD mouse model. Such decrease in synaptic proteins was recovered by CDK5 silencing in mice leading to a better learning and memory performance. Additionally, CDK5 inhibition or knockout increased p120 ctn levels. Moreover, in a glutamate-induced excitotoxicity model, CDK5 silencing-induced neuroprotection depended on p120 ctn. Together, those findings suggest that p120 ctn plays an important role in the neuronal dysfunction of Alzheimer's disease models and contributes to CDK5 silencing-induced neuroprotection and improvement of memory function. (Figure presented.) p120ctn is part of the synaptic adhesion molecular complex N-cadh/p120ctn/B-ctn/PSD95, and it has a pivotal role in cell adhesion stabilization and dendritic spine modulation. Our data show that synaptic adhesion complex is affected in AD human brains and in AD models. This complex is recovered by the silencing of CDK5, preventing memory dysfunction in an AD mice model and contributing to the neuroprotection in a depend-mode of p120ctn. © 2016 International Society for Neurochemistry

PubMed | University of Chile and Center for Geroscience
Type: | Journal: Scientific reports | Year: 2016

Microtubule-associated protein 1B (MAP1B) is expressed predominantly during the early stages of development of the nervous system, where it regulates processes such as axonal guidance and elongation. Nevertheless, MAP1B expression in the brain persists in adult stages, where it participates in the regulation of the structure and physiology of dendritic spines in glutamatergic synapses. Moreover, MAP1B expression is also found in presynaptic synaptosomal preparations. In this work, we describe a presynaptic phenotype in mature neurons derived from MAP1B knockout (MAP1B KO) mice. Mature neurons express MAP1B, and its deficiency does not alter the expression levels of a subgroup of other synaptic proteins. MAP1B KO neurons display a decrease in the density of presynaptic and postsynaptic terminals, which involves a reduction in the density of synaptic contacts, and an increased proportion of orphan presynaptic terminals. Accordingly, MAP1B KO neurons present altered synaptic vesicle fusion events, as shown by FM4-64 release assay, and a decrease in the density of both synaptic vesicles and dense core vesicles at presynaptic terminals. Finally, an increased proportion of excitatory immature symmetrical synaptic contacts in MAP1B KO neurons was detected. Altogether these results suggest a novel role for MAP1B in presynaptic structure and physiology regulation in vitro.

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