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    SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

    Hartmann, Jakob ORCID logoORCID: https://orcid.org/0000-0002-1960-8177, Bajaj, Thomas, Otten, Joy, Klengel, Claudia, Ebert, Tim, Gellner, Anne-Kathrin, Junglas, Ellen, Hafner, Kathrin, Anderzhanova, Elmira A, Tang, Fiona, Missig, Galen, Rexrode, Lindsay, Trussell, Daniel T ORCID logoORCID: https://orcid.org/0009-0006-8547-3828, Li, Katelyn X, Pöhlmann, Max L, Mackert, Sarah ORCID logoORCID: https://orcid.org/0000-0001-5074-4874, Geiger, Thomas M, Heinz, Daniel E ORCID logoORCID: https://orcid.org/0000-0001-7103-9621, Lardenoije, Roy, Dedic, Nina, McCullough, Kenneth M ORCID logoORCID: https://orcid.org/0000-0003-4908-2302, Próchnicki, Tomasz, Rhomberg, Thomas ORCID logoORCID: https://orcid.org/0000-0002-4382-999X, Martinelli, Silvia ORCID logoORCID: https://orcid.org/0000-0002-8784-2213, Payton, Antony ORCID logoORCID: https://orcid.org/0000-0003-0335-152X, Robinson, Andrew C ORCID logoORCID: https://orcid.org/0000-0003-2208-7728, Stein, Valentin ORCID logoORCID: https://orcid.org/0000-0003-1222-4928, Latz, Eicke ORCID logoORCID: https://orcid.org/0000-0003-1488-5666, Carlezon, William A, Hausch, Felix, Schmidt, Mathias V ORCID logoORCID: https://orcid.org/0000-0002-3788-2268, Murgatroyd, Chris ORCID logoORCID: https://orcid.org/0000-0002-6885-7794, Berretta, Sabina, Klengel, Torsten ORCID logoORCID: https://orcid.org/0000-0001-7045-9229, Pantazopoulos, Harry, Ressler, Kerry J ORCID logoORCID: https://orcid.org/0000-0002-5158-1103 and Gassen, Nils C ORCID logoORCID: https://orcid.org/0000-0002-4265-3398 (2024) SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration. Nature Ccommunications, 15 (1). 2635.

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    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.

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