Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.

Autor: Cabral-Miranda F; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.; Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Tamburini G; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile., Martinez G; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile., Ardiles AO; Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile.; Centro de Neurología Traslacional, Escuela de Medicina, Universidad de Valparaíso, Valparaiso, Chile., Medinas DB; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile., Gerakis Y; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile., Hung MD; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile., Vidal R; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.; Center for Integrative Biology, Universidad Mayor, Santiago, Chile., Fuentealba M; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile., Miedema T; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile., Duran-Aniotz C; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile., Diaz J; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile., Ibaceta-Gonzalez C; Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile., Sabusap CM; Departments of Chemistry and Biological Sciences, Vanderbilt University, Nashville, TN, USA., Bermedo-Garcia F; Department of Cell Biology, Center for Advanced Microscopy (CMA BioBio), Universidad de Concepción, Concepción, Chile., Mujica P; Centro de Neurología Traslacional, Escuela de Medicina, Universidad de Valparaíso, Valparaiso, Chile., Adamson S; Buck Institute for Research on Aging, Novato, CA, USA., Vitangcol K; Buck Institute for Research on Aging, Novato, CA, USA., Huerta H; Center for Integrative Biology, Universidad Mayor, Santiago, Chile., Zhang X; Department of Molecular Medicine and Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, USA., Nakamura T; Department of Molecular Medicine and Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, USA., Sardi SP; Rare and Neurological Diseases Therapeutic Area, Sanofi, Framingham, MA, USA., Lipton SA; Department of Molecular Medicine and Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, USA.; Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA., Kennedy BK; Buck Institute for Research on Aging, Novato, CA, USA.; Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore; Centre for Healthy Longevity, National University Health System; Departments of Biochemistry and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Henriquez JP; Department of Cell Biology, Center for Advanced Microscopy (CMA BioBio), Universidad de Concepción, Concepción, Chile., Cárdenas JC; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Center for Integrative Biology, Universidad Mayor, Santiago, Chile.; Buck Institute for Research on Aging, Novato, CA, USA., Plate L; Departments of Chemistry and Biological Sciences, Vanderbilt University, Nashville, TN, USA., Palacios AG; Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile., Hetz C; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.; Buck Institute for Research on Aging, Novato, CA, USA.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2022 Nov 17; Vol. 41 (22), pp. e111952. Date of Electronic Publication: 2022 Oct 31.
DOI: 10.15252/embj.2022111952
Abstrakt: Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.
(© 2022 The Authors.)
Databáze: MEDLINE
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