Browsing by Author "Alvarez, Alejandra"

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    Asymptomatic herpes simplex virus brain infection elicits cellular senescence phenotypes in the central nervous system of mice suffering multiple sclerosis-like disease
    (2024) Duarte, Luisa F.; Villalobos, Veronica; Farias, Monica A.; Rangel-Ramirez, Ma. Andreina; Gonzalez-Madrid, Enrique; Navarro, Areli J.; Carbone-Schellman, Javier; Dominguez, Angelica; Alvarez, Alejandra; Riedel, Claudia A.; Bueno, Susan M.; Kalergis, Alexis M.; Caceres, Monica; Gonzalez, Pablo A.
    Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease affecting the central nervous system (CNS) in animals that parallels several clinical and molecular traits of multiple sclerosis in humans. Herpes simplex virus type 1 (HSV-1) infection mainly causes cold sores and eye diseases, yet eventually, it can also reach the CNS, leading to acute encephalitis. Notably, a significant proportion of healthy individuals are likely to have asymptomatic HSV-1 brain infection with chronic brain inflammation due to persistent latent infection in neurons. Because cellular senescence is suggested as a potential factor contributing to the development of various neurodegenerative disorders, including multiple sclerosis, and viral infections may induce a premature senescence state in the CNS, potentially increasing susceptibility to such disorders, here we examine the presence of senescence-related markers in the brains and spinal cords of mice with asymptomatic HSV-1 brain infection, EAE, and both conditions. Across all scenarios, we find a significant increases of senescence biomarkers in the CNS with some differences depending on the analyzed group. Notably, some senescence biomarkers are exclusively observed in mice with the combined conditions. These results indicate that asymptomatic HSV-1 brain infection and EAE associate with a significant expression of senescence biomarkers in the CNS.
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    Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response
    (2020) Dufey, Estefanie; Bravo-San Pedro, Jose Manuel; Eggers, Cristian; Gonzalez-Quiroz, Matias; Urra, Hery; Sagredo, Alfredo, I; Sepulveda, Denisse; Pihan, Philippe; Carreras-Sureda, Amado; Hazari, Younis; Sagredo, Eduardo A.; Gutierrez, Daniela; Valls, Cristian; Papaioannou, Alexandra; Acosta-Alvear, Diego; Campos, Gisela; Domingos, Pedro M.; Pedeux, Remy; Chevet, Eric; Alvarez, Alejandra; Godoy, Patricio; Walter, Peter; Glavic, Alvaro; Kroemer, Guido; Hetz, Claudio
    The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1 alpha under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1 alpha signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1 alpha -dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1 alpha endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1 alpha to catalyze RIDD. The protective role of IRE1 alpha under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis. IRE1 alpha plays a key role in the unfolded protein response (UPR) by promoting the unconventional splicing of the XBP1 and the selective cleavage of RNAs. Here the authors report that IRE1 alpha is activated upon the DNA damage response and selectively controls the stability of mRNAs to maintain genome integrity.
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    Gold Nanoparticles Mediate Improved Detection of β-amyloid Aggregates by Fluorescence
    (2020) Jara-Guajardo, Pedro; Cabrera, Pablo; Celis, Freddy; Soler, Monica; Berlanga, Isadora; Parra-Munoz, Nicole; Acosta, Gerardo; Albericio, Fernando; Guzman, Fanny; Campos, Marcelo; Alvarez, Alejandra; Morales-Zavala, Francisco; Kogan, Marcelo J.
    The early detection of the amyloid beta peptide aggregates involved in Alzheimer's disease is crucial to test new potential treatments. In this research, we improved the detection of amyloid beta peptide aggregates in vitro and ex vivo by fluorescence combining the use of CRANAD-2 and gold nanorods (GNRs) by the surface enhancement fluorescence effect. We synthetized GNRs and modified their surface with HS-PEG-OMe and HS-PEG-COOH and functionalized them with the D1 peptide, which has the capability to selectively bind to amyloid beta peptide. For an in vitro detection of amyloid beta peptide, we co-incubated amyloid beta peptide aggregates with the probe CRANAD-2 and GNR-PEG-D1 observing an increase in the intensity of the fluorescence signal attributed to surface enhancement fluorescence. Furthermore, the surface enhancement fluorescence effect was observed in brain slices of transgenic mice with Alzheimer's disease co-incubated with CRANAD-2 and GNR-PEG-D1. An increase in the fluorescence signal was observed allowing the detection of aggregates that cannot be detected with the single use of CRANAD-2. Gold nanoparticles allowed an improvement in the detection of the amyloid aggregated by fluorescence in vitro and ex vivo.
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    Heparin activates Wnt signaling for neuronal morphogenesis
    (WILEY, 2008) Colombres, Marcela; Henriquez, Juan Pablo; Reig, German F.; Scheu, Jessica; Calderon, Rosario; Alvarez, Alejandra; Brandan, Enrique; Inestrosa, Nibaldo C.
    Writ factors are secreted ligands that affect different aspects of the nervous system behavior like neurodevelopment, synaptogenesis and neurodegeneration. In different model systems, Wnt signaling has been demonstrated to be regulated by heparan sulfate proteoglycans (HSPGs). Whether HSPGs modulate Writ signaling in the context of neuronal behavior is currently unknown. Here we demonstrate that activation of Wnt signaling with the endogenous ligand Wnt-7a results in an increased of neurite outgrowth in the neuroblastoma N2a cell line. Interestingly, heparin induces glycogen synthase kinase-3 beta (GSK-3 beta) inhibition, beta-catenin stabilization and morphological differentiation in both N2a cells and in rat primary hippocampal neuronal cultures. We also show that heparin modulates Wnt-3a-induced stabilization of beta-catenin. Several extracellular matrix and membrane-attached HSPGs were found to be expressed in both in vitro neuronal models. Changes in the expression of specific HSPGs were observed upon differentiation of N2a cells. Taken together, our findings suggest that HSPGs may modulate canonical Writ signaling for neuronal morphogenesis.
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    Surface enhanced fluorescence effect improves the in vivo detection of amyloid aggregates
    (2022) Cabrera, Pablo; Jara-Guajardo, Pedro; Oyarzun, Maria Paz; Parra-Munoz, Nicole; Campos, Aldo; Soler, Monica; Alvarez, Alejandra; Morales-Zavala, Francisco; Araya, Eyleen; Minniti, Alicia N.; Aldunate, Rebeca; Kogan, Marcelo J.
    The beta-amyloid (A beta) peptide is one of the key etiological agents in Alzheimer's disease (AD). The in vivo detection of A beta species is challenging in all stages of the illness. Currently, the development of fluorescent probes allows the detection of A beta in animal models in the near-infrared region (NIR). However, considering future applications in biomedicine, it is relevant to develop strategies to improve detection of amyloid aggregates using NIR probes. An innovative approach to increase the fluorescence signal of these fluorophores is the use of plasmonic gold nanoparticles (surface-enhanced fluorescence effect). In this work, we improved the detection of A beta aggregates in C. elegans and mouse models of AD by co-administering functionalized gold nanorods (GNRs-PEG-D1) with the fluorescent probes CRANAD-2 or CRANAD-58, which bind selectively to different amyloid species (soluble and insoluble). This work shows that GNRs improve the detection of A beta using NIR probes in vivo. (C) 2022 Published by Elsevier Inc.