TY  - JOUR
AU  - Woo, Marcel S
AU  - Brand, Johannes
AU  - Bal, Lukas C
AU  - Moritz, Manuela
AU  - Walkenhorst, Mark
AU  - Vieira, Vanessa
AU  - Ipenberg, Inbal
AU  - Rothammer, Nicola
AU  - Wang, Man
AU  - Dogan, Batuhan
AU  - Loreth, Desirée
AU  - Mayer, Christina
AU  - Nagel, Darwin
AU  - Wagner, Ingrid
AU  - Pfeffer, Lena Kristina
AU  - Landgraf, Peter
AU  - van Ham, Marco
AU  - Mattern, Kuno M-J
AU  - Winschel, Ingo
AU  - Frantz, Noah
AU  - Sonner, Jana K
AU  - Grosshans, Henrike K
AU  - Miguela, Albert
AU  - Bauer, Simone
AU  - Meurs, Nina
AU  - Müller, Anke
AU  - Binkle-Ladisch, Lars
AU  - Salinas, Gabriela
AU  - Jänsch, Lothar
AU  - Dieterich, Daniela C
AU  - Riedner, Maria
AU  - Krüger, Elke
AU  - Heppner, Frank L
AU  - Glatzel, Markus
AU  - Puelles, Victor G
AU  - Engler, Jan Broder
AU  - Nyengaard, Jens Randel
AU  - Misgeld, Thomas
AU  - Kerschensteiner, Martin
AU  - Merkler, Doron
AU  - Meyer-Schwesinger, Catherine
AU  - Friese, Manuel A
TI  - The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis.
JO  - Cell
VL  - 188
IS  - 17
SN  - 0092-8674
CY  - [Cambridge, Mass.]
PB  - Cell Press
M1  - DZNE-2025-00971
SP  - 4567 - 4585.e32
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Proteasome Endopeptidase Complex: metabolism
KW  - Proteasome Endopeptidase Complex: genetics
KW  - Multiple Sclerosis: metabolism
KW  - Multiple Sclerosis: pathology
KW  - Multiple Sclerosis: immunology
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Mice
KW  - Phosphofructokinase-2: metabolism
KW  - Glycolysis
KW  - Humans
KW  - Interferon-gamma: metabolism
KW  - Mice, Inbred C57BL
KW  - Inflammation: metabolism
KW  - Disease Models, Animal
KW  - Pentose Phosphate Pathway
KW  - Ferroptosis
KW  - Neurodegenerative Diseases: metabolism
KW  - Male
KW  - Female
KW  - Encephalomyelitis, Autoimmune, Experimental
KW  - excitotoxicity (Other)
KW  - ferroptosis (Other)
KW  - glycolysis (Other)
KW  - immunoproteasome (Other)
KW  - interferon-γ (Other)
KW  - metabolism (Other)
KW  - multiple sclerosis (Other)
KW  - neurodegeneration (Other)
KW  - neuroinflammation (Other)
KW  - Proteasome Endopeptidase Complex (NLM Chemicals)
KW  - Phosphofructokinase-2 (NLM Chemicals)
KW  - Interferon-gamma (NLM Chemicals)
KW  - PFKFB3 protein, mouse (NLM Chemicals)
KW  - Psmb10 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40532699
DO  - DOI:10.1016/j.cell.2025.05.029
UR  - https://pub.dzne.de/record/280787
ER  -