SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration
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Published:2024-03-25
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Hartmann JakobORCID, 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, Li Katelyn X., Pöhlmann Max L., Mackert SarahORCID, Geiger Thomas M., Heinz Daniel E.ORCID, Lardenoije Roy, Dedic Nina, McCullough Kenneth M.ORCID, Próchnicki Tomasz, Rhomberg ThomasORCID, Martinelli SilviaORCID, Payton AntonyORCID, Robinson Andrew C.ORCID, Stein ValentinORCID, Latz EickeORCID, Carlezon William A., Hausch Felix, Schmidt Mathias V.ORCID, Murgatroyd ChrisORCID, Berretta Sabina, Klengel TorstenORCID, Pantazopoulos Harry, Ressler Kerry J.ORCID, Gassen Nils C.ORCID
Abstract
AbstractHigh 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.
Publisher
Springer Science and Business Media LLC
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