Nature Communications (Mar 2024)
SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration
- Jakob Hartmann,
- Thomas Bajaj,
- Joy Otten,
- Claudia Klengel,
- Tim Ebert,
- Anne-Kathrin Gellner,
- Ellen Junglas,
- Kathrin Hafner,
- Elmira A. Anderzhanova,
- Fiona Tang,
- Galen Missig,
- Lindsay Rexrode,
- Daniel T. Trussell,
- Katelyn X. Li,
- Max L. Pöhlmann,
- Sarah Mackert,
- Thomas M. Geiger,
- Daniel E. Heinz,
- Roy Lardenoije,
- Nina Dedic,
- Kenneth M. McCullough,
- Tomasz Próchnicki,
- Thomas Rhomberg,
- Silvia Martinelli,
- Antony Payton,
- Andrew C. Robinson,
- Valentin Stein,
- Eicke Latz,
- William A. Carlezon,
- Felix Hausch,
- Mathias V. Schmidt,
- Chris Murgatroyd,
- Sabina Berretta,
- Torsten Klengel,
- Harry Pantazopoulos,
- Kerry J. Ressler,
- Nils C. Gassen
Affiliations
- Jakob Hartmann
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Thomas Bajaj
- Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn
- Joy Otten
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Claudia Klengel
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Tim Ebert
- Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn
- Anne-Kathrin Gellner
- Department of Psychiatry and Psychotherapy, University of Bonn
- Ellen Junglas
- Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn
- Kathrin Hafner
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry
- Elmira A. Anderzhanova
- Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn
- Fiona Tang
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Galen Missig
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Lindsay Rexrode
- Department of Psychiatry and Human Behavior, University of Mississippi Medical Center
- Daniel T. Trussell
- Department of Psychiatry and Human Behavior, University of Mississippi Medical Center
- Katelyn X. Li
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Max L. Pöhlmann
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Sarah Mackert
- Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn
- Thomas M. Geiger
- Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt
- Daniel E. Heinz
- Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn
- Roy Lardenoije
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Nina Dedic
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Kenneth M. McCullough
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Tomasz Próchnicki
- Institute of Innate Immunity, University Hospital Bonn
- Thomas Rhomberg
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Silvia Martinelli
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry
- Antony Payton
- Division of Informatics, Imaging and Data Sciences, University of Manchester
- Andrew C. Robinson
- Division of Neuroscience, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital
- Valentin Stein
- Institute of Physiology II, University of Bonn
- Eicke Latz
- Institute of Innate Immunity, University Hospital Bonn
- William A. Carlezon
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Felix Hausch
- Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt
- Mathias V. Schmidt
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry
- Chris Murgatroyd
- Department of Life Sciences, Manchester Metropolitan University
- Sabina Berretta
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Torsten Klengel
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Harry Pantazopoulos
- Department of Psychiatry and Human Behavior, University of Mississippi Medical Center
- Kerry J. Ressler
- Department of Psychiatry, Harvard Medical School, McLean Hospital
- Nils C. Gassen
- Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn
- DOI
- https://doi.org/10.1038/s41467-024-46953-x
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 20
Abstract
Abstract 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.
