Journal Article

DZNE-2025-00971

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis.

Woo, M. S. ; Brand, J. ; Bal, L. C. ; Moritz, M. ; Walkenhorst, M. ; Vieira, V. ; Ipenberg, I. ; Rothammer, N. ; Wang, M. ; Dogan, B. ; Loreth, D. ; Mayer, C. ; Nagel, D. ; Wagner, I. ; Pfeffer, L. K. ; Landgraf, P. ; van Ham, M. ; Mattern, K. M. ; Winschel, I. ; Frantz, N. ; Sonner, J. K. ; Grosshans, H. K. ; Miguela, A. ; Bauer, S. ; Meurs, N. ; Müller, A. ; Binkle-Ladisch, L. ; Salinas, G. ; Jänsch, L. ; Dieterich, D. C. ; Riedner, M. ; Krüger, E. ; Heppner, F. L.DZNE* ; Glatzel, M. ; Puelles, V. G. ; Engler, J. B. ; Nyengaard, J. R. ; Misgeld, T.DZNE* ; Kerschensteiner, M. ; Merkler, D. ; Meyer-Schwesinger, C. ; Friese, M. A.

2025
Cell Press [Cambridge, Mass.]

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Please use a persistent id in citations: 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.

Keyword(s): Animals (MeSH) ; Proteasome Endopeptidase Complex: metabolism (MeSH) ; Proteasome Endopeptidase Complex: genetics (MeSH) ; Multiple Sclerosis: metabolism (MeSH) ; Multiple Sclerosis: pathology (MeSH) ; Multiple Sclerosis: immunology (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: pathology (MeSH) ; Mice (MeSH) ; Phosphofructokinase-2: metabolism (MeSH) ; Glycolysis (MeSH) ; Humans (MeSH) ; Interferon-gamma: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Inflammation: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Pentose Phosphate Pathway (MeSH) ; Ferroptosis (MeSH) ; Neurodegenerative Diseases: metabolism (MeSH) ; Male (MeSH) ; Female (MeSH) ; Encephalomyelitis, Autoimmune, Experimental (MeSH) ; excitotoxicity ; ferroptosis ; glycolysis ; immunoproteasome ; interferon-γ ; metabolism ; multiple sclerosis ; neurodegeneration ; neuroinflammation ; Proteasome Endopeptidase Complex ; Phosphofructokinase-2 ; Interferon-gamma ; PFKFB3 protein, mouse ; Psmb10 protein, mouse

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Contributing Institute(s):

1. Neuroimmunology (AG Heppner)
2. Neuronal Cell Biology (AG Misgeld)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 60 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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