SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

Hartmann, J.; Bajaj, T.; Otten, J.; Klengel, C.; Gellner, A.-K.; Junglas, E.; Hafner, K.; Anderzhanova, E. A.; Tang, F.; Missig, G.; Rexrode, L.; Li, K.; Poehlmann, M. L.; Heinz, D. E.; Lardenoije, R.; Dedic, N.; McCullough, K. M.; Prochnicki, T.; Rhomberg, T.; Martinelli, S.; Payton, A.; Robinson, A. C.; Stein, V.; Latz, E.; Carlezon, W. A.; Schmidt, M. V.; Murgatroyd, C.; Berretta, S.; Klengel, T.; Pantazopoulos, H.; Ressler, K. J.; Gassen, N. C.

doi:10.1101/2023.04.03.534570

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bioRxiv · 10.1101/2023.04.03.534570

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

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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. We demonstrate 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-1{beta} release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1{beta} release, initiating an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D (GSDMD)-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of postmortem brains demonstrate that SA is hyperactivated in Alzheimers disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimers disease, providing new mechanistic insight into the biology of neuroinflammation.

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Hartmann, J., Bajaj, T., Otten, J., Klengel, C., Gellner, A.-K., Junglas, E., Hafner, K., Anderzhanova, E. A., Tang, F., Missig, G., Rexrode, L., Li, K., Poehlmann, M. L., Heinz, D. E., Lardenoije, R., Dedic, N., McCullough, K. M., Prochnicki, T., Rhomberg, T., Martinelli, S., Payton, A., Robinson, A. C., Stein, V., Latz, E., Carlezon, W. A., Schmidt, M. V., Murgatroyd, C., Berretta, S., Klengel, T., Pantazopoulos, H., Ressler, K. J., Gassen, N. C.. 2023-04-03. SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration. https://doi.org/10.1101/2023.04.03.534570

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