Skip to main content

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.

Nature communications

Authors: 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

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).

PMID: 38528004

Participating cluster members