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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. 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.

SUBMITTER: Hartmann J

PROVIDER: S-EPMC10963788 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.

Hartmann Jakob J Bajaj Thomas T Otten Joy J Klengel Claudia C Ebert Tim T Gellner Anne-Kathrin AK Junglas Ellen E Hafner Kathrin K Anderzhanova Elmira A EA Tang Fiona F Missig Galen G Rexrode Lindsay L Trussell Daniel T DT Li Katelyn X KX Pöhlmann Max L ML Mackert Sarah S Geiger Thomas M TM Heinz Daniel E DE Lardenoije Roy R Dedic Nina N McCullough Kenneth M KM Próchnicki Tomasz T Rhomberg Thomas T Martinelli Silvia S Payton Antony A Robinson Andrew C AC Stein Valentin V Latz Eicke E Carlezon William A WA Hausch Felix F Schmidt Mathias V MV Murgatroyd Chris C Berretta Sabina S Klengel Torsten T Pantazopoulos Harry H Ressler Kerry J KJ Gassen Nils C NC

Nature communications 20240325 1

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 hyperact ...[more]

PMID: 38528004

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Project description:BackgroundDeoxyribonuclease 2 (DNase II) is pivotal in the clearance of cytoplasmic double stranded DNA (dsDNA). Its deficiency incurs DNA accumulation in cytoplasm, which is a hallmark of multiple neurodegenerative diseases. Our previous study showed that neuronal DNase II deficiency drove tau hyperphosphorylation and neurodegeneration (Li et al., Transl Neurodegener 13:39, 2024). Although it has been verified that DNase II participates in type I interferons (IFN-I) mediated autoinflammation and senescence in peripheral systems, the role of microglial DNase II in neuroinflammation and neurodegenerative diseases such as Alzheimer's disease (AD) is still unknown.MethodsThe levels of microglial DNase II in triple transgenic AD mice (3xTg-AD) were measured by immunohistochemistry. The cognitive performance of microglial DNase II deficient WT and AD mice was determined using the Morris water maze test, Y-maze test, novel object recognition test and open filed test. To investigate the impact of microglial DNase II deficiency on microglial morphology, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and IFN-I pathway, neuroinflammation, synapses loss, amyloid pathology and tauopathy, the levels of cGAS-STING and IFN-I pathway related protein, gliosis and proinflammatory cytokines, synaptic protein, complement protein, Aβ levels, phosphorylated tau in the brains of the microglial DNase II deficient WT and AD mice were evaluated by immunolabeling, immunoblotting, q-PCR or ELISA.ResultsWe found that the levels of DNase II were significantly decreased in the microglia of 3xTg-AD mice. Microglial DNase II deficiency altered microglial morphology and transcriptional signatures, activated the cGAS-STING and IFN-I pathway, initiated neuroinflammation, led to synapse loss via complement-dependent pathway, increased Aβ levels and tauopathy, and induced cognitive decline.ConclusionsOur study shows the effect of microglial DNase II deficiency and cytoplasmic accumulated dsDNA on neuroinflammation, and reveals the initiatory mechanism of AD pathology, suggesting that DNase II is a potential target for neurodegenerative diseases.

Project description:Neuroinflammation and neurodegeneration are key components in the establishment and progression of neurodegenerative diseases including Alzheimer's Disease (AD). Over the past decade increasing evidence is emerging for the use of components of the canonical autophagy machinery in pathways that are characterized by LC3 lipidation yet are distinct from traditional macro-autophagy. One such pathway that utilizes components of the autophagy machinery to target LC3 to endosomes, a process termed LC3-associated endocytosis (LANDO), has recently been identified and regulates neuroinflammation. Abrogation of LANDO in microglia cells results in a propensity for elevated neuroinflammatory cytokine production. Using the well-established 5xFAD model of AD to interrogate neuroinflammatory regulation, impairment of LANDO through deletion of a key upstream regulator Rubicon or other downstream autophagy components, exacerbated disease onset and severity, while deletion of microglial autophagy alone had no measurable effect. Mice presented with robust deposition of the neurotoxic AD protein β-amyloid (Aβ), microglial activation and inflammatory cytokine production, tau phosphorylation, and aggressive neurodegeneration culminating in severe memory impairment. LANDO-deficiency impaired recycling of receptors that recognize Aβ, including TLR4 and TREM2. LANDO-deficiency alone through deletion of the WD-domain of the autophagy protein ATG16L, revealed a role for LANDO in the spontaneous establishment of age-associated AD. LANDO-deficient mice aged to 2 years presented with advanced AD-like disease and pathology correlative to that observed in human AD patients. Together, these studies illustrate an important role for microglial LANDO in regulating CNS immune activation and protection against neurodegeneration. New evidence is emerging that demonstrates a putative linkage between pathways such as LANDO and cell death regulation via apoptosis and possibly necroptosis. Herein, we provide a review of the use of the autophagy machinery in non-canonical mechanisms that alter immune regulation and could have significant impact in furthering our understanding of not only CNS diseases like AD, but likely beyond.

Dataset Information

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.

Publications

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.

Similar Datasets

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