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@ARTICLE{Woo:280787,
      author       = {Woo, Marcel S and Brand, Johannes and Bal, Lukas C and
                      Moritz, Manuela and Walkenhorst, Mark and Vieira, Vanessa
                      and Ipenberg, Inbal and Rothammer, Nicola and Wang, Man and
                      Dogan, Batuhan and Loreth, Desirée and Mayer, Christina and
                      Nagel, Darwin and Wagner, Ingrid and Pfeffer, Lena Kristina
                      and Landgraf, Peter and van Ham, Marco and Mattern, Kuno M-J
                      and Winschel, Ingo and Frantz, Noah and Sonner, Jana K and
                      Grosshans, Henrike K and Miguela, Albert and Bauer, Simone
                      and Meurs, Nina and Müller, Anke and Binkle-Ladisch, Lars
                      and Salinas, Gabriela and Jänsch, Lothar and Dieterich,
                      Daniela C and Riedner, Maria and Krüger, Elke and Heppner,
                      Frank L and Glatzel, Markus and Puelles, Victor G and
                      Engler, Jan Broder and Nyengaard, Jens Randel and Misgeld,
                      Thomas and Kerschensteiner, Martin and Merkler, Doron and
                      Meyer-Schwesinger, Catherine and Friese, Manuel A},
      title        = {{T}he immunoproteasome disturbs neuronal metabolism and
                      drives neurodegeneration in multiple sclerosis.},
      journal      = {Cell},
      volume       = {188},
      number       = {17},
      issn         = {0092-8674},
      address      = {[Cambridge, Mass.]},
      publisher    = {Cell Press},
      reportid     = {DZNE-2025-00971},
      pages        = {4567 - 4585.e32},
      year         = {2025},
      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     = {Animals / Proteasome Endopeptidase Complex: metabolism /
                      Proteasome Endopeptidase Complex: genetics / Multiple
                      Sclerosis: metabolism / Multiple Sclerosis: pathology /
                      Multiple Sclerosis: immunology / Neurons: metabolism /
                      Neurons: pathology / Mice / Phosphofructokinase-2:
                      metabolism / Glycolysis / Humans / Interferon-gamma:
                      metabolism / Mice, Inbred C57BL / Inflammation: metabolism /
                      Disease Models, Animal / Pentose Phosphate Pathway /
                      Ferroptosis / Neurodegenerative Diseases: metabolism / Male
                      / Female / Encephalomyelitis, Autoimmune, Experimental /
                      excitotoxicity (Other) / ferroptosis (Other) / glycolysis
                      (Other) / immunoproteasome (Other) / interferon-γ (Other) /
                      metabolism (Other) / multiple sclerosis (Other) /
                      neurodegeneration (Other) / neuroinflammation (Other) /
                      Proteasome Endopeptidase Complex (NLM Chemicals) /
                      Phosphofructokinase-2 (NLM Chemicals) / Interferon-gamma
                      (NLM Chemicals) / PFKFB3 protein, mouse (NLM Chemicals) /
                      Psmb10 protein, mouse (NLM Chemicals)},
      cin          = {AG Heppner / AG Misgeld},
      ddc          = {610},
      cid          = {I:(DE-2719)1810007 / I:(DE-2719)1110000-4},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 351 -
                      Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40532699},
      doi          = {10.1016/j.cell.2025.05.029},
      url          = {https://pub.dzne.de/record/280787},
}