Glycogen synthase kinase-3β regulates fractalkine production by altering its trafficking from Golgi to plasma membrane: implications for Alzheimer's disease.
Cellular and molecular life sciences : CMLS
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Fuster-Matanzo, A., Jurado-Arjona, J., Benvegnù, S., García, E., Martín-Maestro, P., Gómez-Sintes, R., Hernández, F., & et al. (2017). Glycogen synthase kinase-3β regulates fractalkine production by altering its trafficking from Golgi to plasma membrane: implications for Alzheimer's disease.. Cellular and molecular life sciences : CMLS, 74 1153-1163. https://doi.org/10.1007/s00018-016-2408-6
Glycogen synthase kinase-3β (GSK-3β) is a serine-threonine kinase implicated in multiple processes and signaling pathways. Its dysregulation is associated with different pathological conditions including Alzheimer's disease (AD). Here we demonstrate how changes in GSK-3β activity and/or levels regulate the production and subsequent secretion of fractalkine, a chemokine involved in the immune response that has been linked to AD and to other different neurological disorders. Treatment of primary cultured neurons with GSK-3β inhibitors such as lithium and AR-A014418 decreased full-length fractalkine in total cell extracts. Opposite effects were observed after neuron transduction with a lentiviral vector overexpressing the kinase. Biotinylation assays showed that those changes mainly affect the plasma membrane-associated form of the protein, an observation that positively correlates with changes in the levels of its soluble form. These effects were confirmed in lithium-treated wild type (wt) mice and in GSK-3β transgenic animals, as well as in brain samples from AD patients, evident as age-dependent (animals) or Braak stage dependent changes (humans) in both the membrane-bound and the soluble forms of the protein. Further immunohistochemical analyses demonstrated how GSK-3β exerts these effects by affecting the trafficking of the chemokine from the Golgi to the plasma membrane, in different and opposite ways when the levels/activity of the kinase are increased or decreased. This work provides for the first time a mechanism linking GSK-3β and fractalkine both in vitro and in vivo, with important implications for neurological disorders and especially for AD, in which levels of this chemokine might be useful as a diagnostic tool.
Cell Membrane, Transport Vesicles, Golgi Apparatus, Animals, Mice, Inbred C57BL, Humans, Alzheimer Disease, rab GTP-Binding Proteins, Protein Binding, Protein Transport, Solubility, Chemokine CX3CL1, Glycogen Synthase Kinase 3 beta
This study was funded by grants from Spanish Ministry of Economy and Competitiveness (SAF 2006-02424, BFU-2008-03980, BFU-2010-21507), Comunidad de Madrid (SAL/0202/2006), Fundación M. Botín, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), and an institutional grant from the Fundación R. Areces. Authors would like to thank Dr. Alberto Rábano (Neuropathology Department, CIEN Foundation, Madrid, Spain) for the human brain samples, people from Laboratory 122 from the Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain, for the constant help and technical support and Dr. Jayden A. Smith (Clinical Neurosciences Deparment, University of Cambridge) for kindly revising and correcting English grammar.
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External DOI: https://doi.org/10.1007/s00018-016-2408-6
This record's URL: https://www.repository.cam.ac.uk/handle/1810/262089
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International