2. Academic Validation
  3. The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis

The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis

  • Cell. 2025 Jun 13:S0092-8674(25)00616-6. doi: 10.1016/j.cell.2025.05.029.
Marcel S Woo 1,  Johannes Brand 2,  Lukas C Bal 1,  Manuela Moritz 3,  Mark Walkenhorst 1,  Vanessa Vieira 1,  Inbal Ipenberg 1,  Nicola Rothammer 1,  Man Wang 2,  Batuhan Dogan 2,  Desirée Loreth 2,  Christina Mayer 1,  Darwin Nagel 1,  Ingrid Wagner 4,  Lena Kristina Pfeffer 1,  Peter Landgraf 5,  Marco van Ham 6,  Kuno M-J Mattern 1,  Ingo Winschel 1,  Noah Frantz 7,  Jana K Sonner 1,  Henrike K Grosshans 1,  Albert Miguela 8,  Simone Bauer 1,  Nina Meurs 1,  Anke Müller 5,  Lars Binkle-Ladisch 1,  Gabriela Salinas 9,  Lothar Jänsch 6,  Daniela C Dieterich 5,  Maria Riedner 10,  Elke Krüger 11,  Frank L Heppner 12,  Markus Glatzel 13,  Victor G Puelles 14,  Jan Broder Engler 1,  Jens Randel Nyengaard 15,  Thomas Misgeld 16,  Martin Kerschensteiner 17,  Doron Merkler 4,  Catherine Meyer-Schwesinger 2,  Manuel A Friese 18
Affiliations

Affiliations

  • 1 Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 2 Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 3 Section/Core Facility Mass Spectrometry and Proteomics, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 4 Department of Pathology and Immunology, Division of Clinical Pathology, Faculty of Medicine, University and University Hospital of Geneva, Geneva, Switzerland.
  • 5 Institute for Pharmacology and Toxicology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
  • 6 Cellular Proteome Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • 7 Center of Hybrid Nanostructures, University of Hamburg, Hamburg, Germany.
  • 8 Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
  • 9 NGS Integrative Genomics Core Unit, University Medical Center Göttingen, Göttingen, Germany.
  • 10 Technology Platform Mass Spectrometry, University of Hamburg, Hamburg, Germany.
  • 11 Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany.
  • 12 Department of Neuropathology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Cluster of Excellence, NeuroCure, Charitéplatz 1, Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
  • 13 Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 14 III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Pathology, Aarhus University Hospital, Aarhus, Denmark.
  • 15 Department of Pathology, Aarhus University Hospital, Aarhus, Denmark; Core Center for Molecular Morphology, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • 16 Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
  • 17 Munich Cluster of Systems Neurology (SyNergy), Munich, Germany; Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany; Biomedical Center, Medical Faculty, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 18 Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: manuel.friese@zmnh.uni-hamburg.de.
PMID: 40532699 DOI: 10.1016/j.cell.2025.05.029
Abstract

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.

Keywords

excitotoxicity; ferroptosis; glycolysis; immunoproteasome; interferon-γ; metabolism; multiple sclerosis; neurodegeneration; neuroinflammation.

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