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 () and Nils C. Gassen ()
Additional contact information
Jakob Hartmann: McLean Hospital
Thomas Bajaj: University of Bonn
Joy Otten: McLean Hospital
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
Fiona Tang: McLean Hospital
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
Sarah Mackert: University of Bonn
Thomas M. Geiger: Technische Universität Darmstadt
Daniel E. Heinz: University of Bonn
Roy Lardenoije: McLean Hospital
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
Valentin Stein: University of Bonn
Eicke Latz: University Hospital Bonn
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
Harry Pantazopoulos: University of Mississippi Medical Center
Kerry J. Ressler: McLean Hospital
Nils C. Gassen: University of Bonn

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-46953-x

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