ArticleNature communications2024
SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.
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Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21citing papers in PubMed
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Who cites it
21 citing papers in PubMed, 26 citations in OpenAlex.
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- HIV Tat-Stimulated Microglial Extracellular Vesicles Are Enriched for Ferroptosis Mediators: Role of Dysregulated Autophagy.Journal of extracellular biology · 2026Article
- A Genome-wide Association Study of Alzheimer's Disease and Dementia in a Large Multi-ancestry Military Cohort Identifies Many New Dementia-Associated Loci.medRxiv : the preprint server for health sciences · 2026Article
- Autophagy-Neuroinflammation Axis in Neurodegenerative Diseases: Mechanisms and Therapeutic Potential.Cells · 2026Review
- Autophagy: A Double-Edged Sword in the Aging ofInternational journal of molecular sciences · 2026Review
- Mechanisms by which sevoflurane affects cognitive function in aged marmosets and mice: up-regulation of FKBP5 expression in brain microglia.Medical gas research · 2026Article
- FKBP5 Orchestrates a Biphasic Microglial Response in Spinal Cord Injury by Sequentially Activating the GPR84/IL-1β Pathway and the LDHA-Lactylation-FXYD5/LGALS1 Axis.Research (Washington, D.C.) · 2026Article
- The Fractalkine (FKN/CX3CL1) Pathway in Depression: A Critical Review of Its Role in Neuroinflammation and Therapeutic Potential.Neuropsychiatric disease and treatment · 2026Review
- LC3-dependent intercellular transfer of phosphorylated STAT1/2 elicits CXCL9+ macrophages and enhances radiation-induced antitumor immunity.The Journal of clinical investigation · 2025Article
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- From intracellular sensors to systemic resilience: Reframing the biology of stress.Neurobiology of stress · 2025Review
- Inborn errors of canonical autophagy in neurodegenerative diseases.Human molecular genetics · 2025Review
- FKBP51 inhibition ameliorates neurodegeneration and motor dysfunction in the neuromelanin-SNCA mouse model of Parkinson's disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Deep phenotyping reveals CRH and FKBP51-dependent behavioral profiles following chronic social stress exposure in male mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Role of FK506 binding protein 51 in central nervous system diseases.Frontiers in molecular neuroscience · 2025Review
- SKA2 enhances stress-related glucocorticoid receptor signaling through FKBP4-FKBP5 interactions in neurons.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- SKArred 2 death: neuroinflammatory breakdown of the hippocampus.Autophagy · 2024Article
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Authors and funding
37 authors at 9 institutions in 3 countries.
Jakob HartmannDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA. jhartmann@mclean.harvard.edu.ORCID http://orcid.org/0000-0002-1960-8177
Thomas BajajResearch Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany.
Joy OttenDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.
Claudia KlengelDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.
Tim EbertResearch Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany.
Anne-Kathrin GellnerDepartment of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany.
Ellen JunglasResearch Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany.
Kathrin HafnerDepartment of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804, Munich, Germany.
Elmira A AnderzhanovaResearch Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany.
Fiona TangDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.
Galen MissigDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.
Lindsay RexrodeDepartment of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
Daniel T TrussellDepartment of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, 39216, USA.ORCID http://orcid.org/0009-0006-8547-3828
Katelyn X LiDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.
Max L PöhlmannDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.
Sarah MackertResearch Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany.ORCID http://orcid.org/0000-0001-5074-4874
Thomas M GeigerInstitute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, 64287, Darmstadt, Germany.
Daniel E HeinzResearch Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany.ORCID http://orcid.org/0000-0001-7103-9621
Roy LardenoijeDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.
Nina DedicDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.
Kenneth M McCulloughDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.ORCID http://orcid.org/0000-0003-4908-2302
Tomasz PróchnickiInstitute of Innate Immunity, University Hospital Bonn, 53127, Bonn, Germany.
Thomas RhombergDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.ORCID http://orcid.org/0000-0002-4382-999X
Silvia MartinelliDepartment of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804, Munich, Germany.ORCID http://orcid.org/0000-0002-8784-2213
Antony PaytonDivision of Informatics, Imaging and Data Sciences, University of Manchester, Manchester, M13 9PL, UK.ORCID http://orcid.org/0000-0003-0335-152X
Andrew C RobinsonDivision of Neuroscience, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.ORCID http://orcid.org/0000-0003-2208-7728
Valentin SteinInstitute of Physiology II, University of Bonn, 53127, Bonn, Germany.ORCID http://orcid.org/0000-0003-1222-4928
Eicke LatzInstitute of Innate Immunity, University Hospital Bonn, 53127, Bonn, Germany.ORCID http://orcid.org/0000-0003-1488-5666
William A CarlezonDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.
Felix HauschInstitute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, 64287, Darmstadt, Germany.
Mathias V SchmidtResearch Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804, Munich, Germany.ORCID http://orcid.org/0000-0002-3788-2268
Chris MurgatroydDepartment of Life Sciences, Manchester Metropolitan University, Manchester, M15 6BH, UK.ORCID http://orcid.org/0000-0002-6885-7794
Sabina BerrettaDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.
Torsten KlengelDepartment of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA.ORCID http://orcid.org/0000-0001-7045-9229
Harry PantazopoulosDepartment of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
Kerry J Ressler *Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA. kressler@mclean.harvard.edu.ORCID http://orcid.org/0000-0002-5158-1103
Nils C Gassen *Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany. nils.gassen@ukbonn.de.ORCID http://orcid.org/0000-0002-4265-3398
Harvard University · USUniversity of Bonn · DEMax Planck Institute of Psychiatry · DEUniversity of Mississippi Medical Center · USTechnische Universität Darmstadt · DEUniversity Hospital Bonn · DEManchester Academic Health Science Centre · GBManchester Metropolitan University · GBUniversity of Manchester · GB
Funding
SPARED CenterP50MH115874 · NIMH · MCLEAN HOSPITAL · PI CARLEZON, WILLIAM A. · 2019 to 2023
$13.7MSite 3/3, Understanding PTSD through Postmortem Targeted Brain MultiomicsR01MH117292 · NIMH · MCLEAN HOSPITAL · PI Nikolaos Daskalakis, KERRY J. RESSLER · 2018 to 2026
$5.0MUnderstanding the transgenerational epigenetic effect of maternal psychosocial trauma exposure on infants via lncRNA-sequencingR01HD102974 · NICHD · MCLEAN HOSPITAL · PI KLENGEL, TORSTEN, KOEN , NASTASSJA · 2020 to 2024
$2.9MLongitudinal DNA methylation in a non-human primate model of early-life stressR21HD088931 · NICHD · MCLEAN HOSPITAL · PI KLENGEL, TORSTEN, RESSLER, KERRY J. · 2017 to 2018
$473kEffects of Stress and Obesity on Longitudinal Epigenetic ProgrammingR21HD097524 · NICHD · MCLEAN HOSPITAL · PI ETHUN, KELLY F, KLENGEL, TORSTEN · 2019 to 2020
$465kA role for circular RNAs in schizophreniaR21MH117609 · NIMH · MCLEAN HOSPITAL · PI BERRETTA, SABINA, KLENGEL, TORSTEN · 2019 to 2020
$451kNICHD NIH HHS R01 HD102974NICHD NIH HHS R21 HD088931NICHD NIH HHS R21 HD097524NIMH NIH HHS P50 MH115874NIMH NIH HHS R01 MH117292NIMH NIH HHS R21 MH117609
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.
Indexed as
Alzheimer DiseaseAutophagyChromosomal Proteins, Non-HistoneNeuroinflammatory DiseasesNLR Family, Pyrin Domain-Containing 3 ProteinAnimalsCytokinesFemaleHumansInflammasomesMaleMiceMicrogliaChromosomal Proteins, Non-HistoneCytokinesInflammasomesNLR Family, Pyrin Domain-Containing 3 ProteinSKA2 protein, human
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