SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.

Autor:	Hartmann J; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA. jhartmann@mclean.harvard.edu., Bajaj T; Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany., Otten J; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37075, Göttingen, Germany., Klengel C; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA., Ebert T; Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany., Gellner AK; Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany., Junglas E; Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany., Hafner K; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804, Munich, Germany., Anderzhanova EA; Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany.; Research Group Neuronal Plasticity, Max Planck Institute of Psychiatry, 80804, Munich, Germany., Tang F; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.; Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany., Missig G; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA., Rexrode L; Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, 39216, USA., Trussell DT; Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, 39216, USA., Li KX; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA., Pöhlmann ML; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.; Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany., Mackert S; Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany., Geiger TM; Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, 64287, Darmstadt, Germany., Heinz DE; Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany.; Research Group Neuronal Plasticity, Max Planck Institute of Psychiatry, 80804, Munich, Germany., Lardenoije R; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37075, Göttingen, Germany., Dedic N; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA., McCullough KM; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA., Próchnicki T; Institute of Innate Immunity, University Hospital Bonn, 53127, Bonn, Germany., Rhomberg T; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA., Martinelli S; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804, Munich, Germany., Payton A; Division of Informatics, Imaging and Data Sciences, University of Manchester, Manchester, M13 9PL, UK., Robinson AC; Division of Neuroscience, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.; Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre (MAHSC), Manchester, UK., Stein V; Institute of Physiology II, University of Bonn, 53127, Bonn, Germany., Latz E; Institute of Innate Immunity, University Hospital Bonn, 53127, Bonn, Germany.; Deutsches Rheuma Forschungszentrum Berlin (DRFZ), 10117, Berlin, Germany., Carlezon WA Jr; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA., Hausch F; Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, 64287, Darmstadt, Germany., Schmidt MV; Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany., Murgatroyd C; Department of Life Sciences, Manchester Metropolitan University, Manchester, M15 6BH, UK., Berretta S; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA., Klengel T; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37075, Göttingen, Germany., Pantazopoulos H; Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, 39216, USA., Ressler KJ; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA. kressler@mclean.harvard.edu., Gassen NC; Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany. nils.gassen@ukbonn.de.; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804, Munich, Germany. nils.gassen@ukbonn.de.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2024 Mar 25; Vol. 15 (1), pp. 2635. Date of Electronic Publication: 2024 Mar 25.
DOI:	10.1038/s41467-024-46953-x
Abstrakt:	High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1β release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1β release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation. (© 2024. The Author(s).)
Databáze:	MEDLINE
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