The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis
Inflammation, aberrant proteostasis, and energy depletion are hallmarks of neurodegenerative diseases such as multiple sclerosis (MS). However, the interplay between inflammation, proteasomal dysfunction in neurons, and its consequences for neuronal integrity remains unclear. Using transcriptional, proteomic, and functional analyses of proteasomal subunits in inflamed neurons, we found that interferon-γ-mediated induction of the immunoproteasome subunit, proteasome 20S beta 8 (PSMB8) impairs the proteasomal balance, resulting in reduced proteasome activity. This reduction causes the accumulation of phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key metabolic regulator, leading to enhanced neuronal glycolysis, reduced pentose phosphate pathway activity, oxidative injury, and ferroptosis. Neuron-specific genetic and systemic pharmacological targeting of PSMB8 or PFKFB3 protected neurons in vitro and in a mouse model of MS. Our findings provide a unifying explanation for proteasomal dysfunction in MS and possibly other neurodegenerative diseases, linking inflammation to metabolic disruption, and presenting an opportunity for targeted neuroprotective therapies.
Authors
- Maria Riedner (ORCID: https://orcid.org/0000-0003-4421-998X)
- Ingrid Wagner (ORCID: https://orcid.org/0000-0003-4437-9799)
- Martin Kerschensteiner (ORCID: https://orcid.org/0000-0003-4898-9383)
- Jan Broder Engler (ORCID: https://orcid.org/0000-0002-3169-2076)
- Manuel Alexander Friese (ORCID: https://orcid.org/0000-0001-6380-2420)
- Lukas C. Bal (ORCID: https://orcid.org/0000-0003-4731-2311)
- Man Wang (ORCID: https://orcid.org/0000-0001-8767-5489)
- Nicola Rothammer (ORCID: https://orcid.org/0000-0002-5137-389X)
- Simone Bauer (ORCID: https://orcid.org/0000-0003-1780-231X)
- Manuela Moritz (ORCID: https://orcid.org/0000-0002-8537-7493)
- Vanessa Vieira (ORCID: https://orcid.org/0000-0002-0205-9669)
- Jens Randel Nyengaard
- Daniela C. Dieterich (ORCID: https://orcid.org/0000-0002-9880-1214)
- Marcel S. Woo (ORCID: https://orcid.org/0000-0002-1306-2708)
- Henrike K. Grosshans (ORCID: https://orcid.org/0000-0001-8294-5494)
- Desirée Loreth (ORCID: https://orcid.org/0000-0003-0827-149X)
- Nina Meurs (ORCID: https://orcid.org/0000-0001-5366-0123)
- Victor G. Puelles (ORCID: https://orcid.org/0000-0002-7735-5462)
- Burcu Doğan (ORCID: https://orcid.org/0000-0002-3817-7560)
- Peter Landgraf (ORCID: https://orcid.org/0000-0003-0793-6875)
- Anke Müller (ORCID: https://orcid.org/0000-0002-6748-5706)
- Christina Mayer (ORCID: https://orcid.org/0000-0002-4148-2822)
- Johannes Brand
- Marco van Ham (ORCID: https://orcid.org/0000-0001-6819-4284)
- Thomas Misgeld (ORCID: https://orcid.org/0000-0001-9875-6794)
- Jana K. Sonner (ORCID: https://orcid.org/0000-0002-4700-272X)
- Ingo Winschel (ORCID: https://orcid.org/0000-0001-9487-7070)
- Markus Glatzel (ORCID: https://orcid.org/0000-0002-7720-8817)
- Inbal Ipenberg
- Catherine Meyer-Schwesinger
- Doron Merkler (ORCID: https://orcid.org/0000-0002-0247-2007)
- Lena Kristina Pfeffer (ORCID: https://orcid.org/0000-0003-3057-6492)
- Lars Binkle-Ladisch (ORCID: https://orcid.org/0000-0001-6168-3210)
- Gabriela Salinas (ORCID: https://orcid.org/0000-0001-8269-2669)
- Frank L. Heppner (ORCID: https://orcid.org/0000-0001-9816-8917)
- Nilo Frantz (ORCID: https://orcid.org/0000-0002-4671-408X)
- Lothar Jänsch (ORCID: https://orcid.org/0000-0002-5655-1181)
- Albert Miguela
- Mark Walkenhorst (ORCID: https://orcid.org/0000-0002-2277-9532)
- Kai Mattern
- Elke Krüger (ORCID: https://orcid.org/0000-0002-2551-242X)
- D Nagel
Institutions
- Universität Hamburg (DE)
- Universitätsmedizin Greifswald (DE)
- Aarhus University Hospital (DK)
- Humboldt-Universität zu Berlin (DE)
- University Hospital of Geneva (CH)
- University Medical Center Hamburg-Eppendorf (DE)
- Munich Cluster for Systems Neurology (DE)
- Universitätsmedizin Göttingen (DE)
- Helmholtz Centre for Infection Research (DE)
- Institute of Neuroimmunology of the Slovak Academy of Sciences (SK)
- HAW Hamburg (DE)
- University of Göttingen (DE)
- Charité - Universitätsmedizin Berlin (DE)
- Ludwig-Maximilians-Universität München (DE)
- Otto-von-Guericke-Universität Magdeburg (DE)
Publication Details
- Journal
- Cell
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1016/j.cell.2025.05.029
- Citations
- 18
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 14.51
Funders
- Deutsche Forschungsgemeinschaft
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Bundesministerium für Bildung und Forschung
- Else Kröner-Fresenius-Stiftung
- Novo Nordisk Fonden
- Novo Nordisk Foundation Center for Basic Metabolic Research
- European Research Council
- H2020 European Research Council