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SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

Jakob Hartmann1, Thomas Bajaj2, Joy Otten3,4

  • 1Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA. jhartmann@mclean.harvard.edu.

Nature Communications
|March 26, 2024
PubMed

Insights

Secretory autophagy (SA) drives neuroinflammation and neurodegeneration by releasing IL-1β. Inhibiting SA via SKA2 is crucial, as its hyperactivation, observed in Alzheimer's disease, causes severe brain atrophy.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Immunology

Background:

  • Proinflammatory cytokines contribute to neurotoxicity and neurodegeneration.
  • Microglial release mechanisms for these cytokines are not fully understood.
  • Autophagy plays a role in cellular secretion and inflammation.

Purpose of the Study:

  • To elucidate the role of secretory autophagy (SA) in neuroinflammation and neurodegeneration.
  • To investigate the involvement of SKA2 and FKBP5 signaling in SA-mediated cytokine release.
  • To determine the link between SA hyperactivation and Alzheimer's disease.

Main Methods:

  • Investigated secretory autophagy (SA) in microglia using mouse models.
  • Utilized hippocampal Ska2 knockdown in male mice.
  • Performed protein expression and co-immunoprecipitation analyses on human postmortem brain samples.

Main Results:

  • Secretory autophagy (SA) regulates neuroinflammation via SKA2 and FKBP5 signaling.
  • Ska2 knockdown in mice led to hyperactivated SA, neuroinflammation, and hippocampal atrophy.
  • Hyperactivated SA increases IL-1β release, NLRP3-inflammasome activation, and Gasdermin D-mediated neurotoxicity.
  • SA was found to be hyperactivated in human Alzheimer's disease brains.

Conclusions:

  • SKA2-regulated secretory autophagy (SA) drives neuroinflammation and neurodegeneration.
  • Hyperactivated SA is mechanistically linked to Alzheimer's disease.
  • Targeting SA presents a potential therapeutic strategy for neuroinflammatory diseases.

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