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SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

Author

Listed:
  • Jakob Hartmann

    (McLean Hospital)

  • Thomas Bajaj

    (University of Bonn)

  • Joy Otten

    (McLean Hospital
    University Medical Center Göttingen)

  • Claudia Klengel

    (McLean Hospital)

  • Tim Ebert

    (University of Bonn)

  • Anne-Kathrin Gellner

    (University of Bonn)

  • Ellen Junglas

    (University of Bonn)

  • Kathrin Hafner

    (Max Planck Institute of Psychiatry)

  • Elmira A. Anderzhanova

    (University of Bonn
    Max Planck Institute of Psychiatry)

  • Fiona Tang

    (McLean Hospital
    Max Planck Institute of Psychiatry)

  • Galen Missig

    (McLean Hospital)

  • Lindsay Rexrode

    (University of Mississippi Medical Center)

  • Daniel T. Trussell

    (University of Mississippi Medical Center)

  • Katelyn X. Li

    (McLean Hospital)

  • Max L. Pöhlmann

    (McLean Hospital
    Max Planck Institute of Psychiatry)

  • Sarah Mackert

    (University of Bonn)

  • Thomas M. Geiger

    (Technische Universität Darmstadt)

  • Daniel E. Heinz

    (University of Bonn
    Max Planck Institute of Psychiatry)

  • Roy Lardenoije

    (McLean Hospital
    University Medical Center Göttingen)

  • Nina Dedic

    (McLean Hospital)

  • Kenneth M. McCullough

    (McLean Hospital)

  • Tomasz Próchnicki

    (University Hospital Bonn)

  • Thomas Rhomberg

    (McLean Hospital)

  • Silvia Martinelli

    (Max Planck Institute of Psychiatry)

  • Antony Payton

    (University of Manchester)

  • Andrew C. Robinson

    (Salford Royal Hospital
    Manchester Academic Health Science Centre (MAHSC))

  • Valentin Stein

    (University of Bonn)

  • Eicke Latz

    (University Hospital Bonn
    Deutsches Rheuma Forschungszentrum Berlin (DRFZ))

  • William A. Carlezon

    (McLean Hospital)

  • Felix Hausch

    (Technische Universität Darmstadt)

  • Mathias V. Schmidt

    (Max Planck Institute of Psychiatry)

  • Chris Murgatroyd

    (Manchester Metropolitan University)

  • Sabina Berretta

    (McLean Hospital)

  • Torsten Klengel

    (McLean Hospital
    University Medical Center Göttingen)

  • Harry Pantazopoulos

    (University of Mississippi Medical Center)

  • Kerry J. Ressler

    (McLean Hospital)

  • Nils C. Gassen

    (University of Bonn
    Max Planck Institute of Psychiatry)

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.

Suggested Citation

  • 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 &, 2024. "SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46953-x
    DOI: 10.1038/s41467-024-46953-x
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    References listed on IDEAS

    as
    1. Xing Liu & Zhibin Zhang & Jianbin Ruan & Youdong Pan & Venkat Giri Magupalli & Hao Wu & Judy Lieberman, 2016. "Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores," Nature, Nature, vol. 535(7610), pages 153-158, July.
    2. Yuan He & Melody Y. Zeng & Dahai Yang & Benny Motro & Gabriel Núñez, 2016. "NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux," Nature, Nature, vol. 530(7590), pages 354-357, February.
    3. Silvia Martinelli & Elmira A. Anderzhanova & Thomas Bajaj & Svenja Wiechmann & Frederik Dethloff & Katja Weckmann & Daniel E. Heinz & Tim Ebert & Jakob Hartmann & Thomas M. Geiger & Michael Döngi & Ka, 2021. "Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    4. Xuran Wang & Jihwan Park & Katalin Susztak & Nancy R. Zhang & Mingyao Li, 2019. "Bulk tissue cell type deconvolution with multi-subject single-cell expression reference," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
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