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SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration
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-1β 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-1β 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 Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing new mechanistic insight into the biology of neuroinflammation.
Insights
Secretory autophagy (SA) drives neuroinflammation and neurodegeneration by releasing inflammatory cytokines. Inhibiting SA offers a potential therapeutic target for Alzheimer's disease and other neuroinflammatory conditions.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Proinflammatory cytokines released by microglia are implicated in neurotoxicity and neurodegeneration.
- The precise mechanisms governing the release of these cytokines from microglia remain unclear.
- Secretory autophagy (SA) is an emerging pathway for cellular cargo release.
Approach:
- Investigated the role of secretory autophagy (SA) in microglial-mediated neuroinflammation.
- Utilized hippocampal Ska2 knockdown in mice to model SA hyperactivation.
- Examined protein expression and co-immunoprecipitation in postmortem Alzheimer's disease brains.
Key Points:
- SA regulates neuroinflammation and neurodegeneration via SKA2 and FKBP5 signaling.
- SKA2 normally inhibits SA-dependent IL-1β release; its knockdown leads to hyperactivated SA.
- Hyperactivated SA triggers a vicious cycle of inflammation, NLRP3-inflammasome activation, and GSDMD-mediated neurotoxicity.
- SA was found to be hyperactivated in postmortem Alzheimer's disease brains.
Conclusions:
- Hyperactivated SA, regulated by SKA2, drives neuroinflammation and neurodegeneration.
- This pathway is mechanistically linked to Alzheimer's disease pathogenesis.
- Targeting SA presents a novel therapeutic strategy for neuroinflammatory diseases.
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