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...
March 25, 2024: Nature Communications