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000280787 1001_ $$aWoo, Marcel S$$b0
000280787 245__ $$aThe immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis.
000280787 260__ $$a[Cambridge, Mass.]$$bCell Press$$c2025
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000280787 520__ $$aInflammation, aberrant proteostasis, and energy depletion are hallmarks of neurodegenerative diseases such as multiple sclerosis (MS). However, the interplay between inflammation, proteasomal dysfunction in neurons, and its consequences for neuronal integrity remains unclear. Using transcriptional, proteomic, and functional analyses of proteasomal subunits in inflamed neurons, we found that interferon-γ-mediated induction of the immunoproteasome subunit, proteasome 20S beta 8 (PSMB8) impairs the proteasomal balance, resulting in reduced proteasome activity. This reduction causes the accumulation of phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key metabolic regulator, leading to enhanced neuronal glycolysis, reduced pentose phosphate pathway activity, oxidative injury, and ferroptosis. Neuron-specific genetic and systemic pharmacological targeting of PSMB8 or PFKFB3 protected neurons in vitro and in a mouse model of MS. Our findings provide a unifying explanation for proteasomal dysfunction in MS and possibly other neurodegenerative diseases, linking inflammation to metabolic disruption, and presenting an opportunity for targeted neuroprotective therapies.
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000280787 650_7 $$2Other$$aexcitotoxicity
000280787 650_7 $$2Other$$aferroptosis
000280787 650_7 $$2Other$$aglycolysis
000280787 650_7 $$2Other$$aimmunoproteasome
000280787 650_7 $$2Other$$ainterferon-γ
000280787 650_7 $$2Other$$ametabolism
000280787 650_7 $$2Other$$amultiple sclerosis
000280787 650_7 $$2Other$$aneurodegeneration
000280787 650_7 $$2Other$$aneuroinflammation
000280787 650_7 $$0EC 3.4.25.1$$2NLM Chemicals$$aProteasome Endopeptidase Complex
000280787 650_7 $$0EC 2.7.1.105$$2NLM Chemicals$$aPhosphofructokinase-2
000280787 650_7 $$082115-62-6$$2NLM Chemicals$$aInterferon-gamma
000280787 650_7 $$0EC 2.7.1.105$$2NLM Chemicals$$aPFKFB3 protein, mouse
000280787 650_7 $$0EC 3.4.25.1$$2NLM Chemicals$$aPsmb10 protein, mouse
000280787 650_2 $$2MeSH$$aAnimals
000280787 650_2 $$2MeSH$$aProteasome Endopeptidase Complex: metabolism
000280787 650_2 $$2MeSH$$aProteasome Endopeptidase Complex: genetics
000280787 650_2 $$2MeSH$$aMultiple Sclerosis: metabolism
000280787 650_2 $$2MeSH$$aMultiple Sclerosis: pathology
000280787 650_2 $$2MeSH$$aMultiple Sclerosis: immunology
000280787 650_2 $$2MeSH$$aNeurons: metabolism
000280787 650_2 $$2MeSH$$aNeurons: pathology
000280787 650_2 $$2MeSH$$aMice
000280787 650_2 $$2MeSH$$aPhosphofructokinase-2: metabolism
000280787 650_2 $$2MeSH$$aGlycolysis
000280787 650_2 $$2MeSH$$aHumans
000280787 650_2 $$2MeSH$$aInterferon-gamma: metabolism
000280787 650_2 $$2MeSH$$aMice, Inbred C57BL
000280787 650_2 $$2MeSH$$aInflammation: metabolism
000280787 650_2 $$2MeSH$$aDisease Models, Animal
000280787 650_2 $$2MeSH$$aPentose Phosphate Pathway
000280787 650_2 $$2MeSH$$aFerroptosis
000280787 650_2 $$2MeSH$$aNeurodegenerative Diseases: metabolism
000280787 650_2 $$2MeSH$$aMale
000280787 650_2 $$2MeSH$$aFemale
000280787 650_2 $$2MeSH$$aEncephalomyelitis, Autoimmune, Experimental
000280787 7001_ $$aBrand, Johannes$$b1
000280787 7001_ $$aBal, Lukas C$$b2
000280787 7001_ $$aMoritz, Manuela$$b3
000280787 7001_ $$aWalkenhorst, Mark$$b4
000280787 7001_ $$aVieira, Vanessa$$b5
000280787 7001_ $$aIpenberg, Inbal$$b6
000280787 7001_ $$aRothammer, Nicola$$b7
000280787 7001_ $$aWang, Man$$b8
000280787 7001_ $$aDogan, Batuhan$$b9
000280787 7001_ $$aLoreth, Desirée$$b10
000280787 7001_ $$aMayer, Christina$$b11
000280787 7001_ $$aNagel, Darwin$$b12
000280787 7001_ $$aWagner, Ingrid$$b13
000280787 7001_ $$aPfeffer, Lena Kristina$$b14
000280787 7001_ $$aLandgraf, Peter$$b15
000280787 7001_ $$avan Ham, Marco$$b16
000280787 7001_ $$aMattern, Kuno M-J$$b17
000280787 7001_ $$aWinschel, Ingo$$b18
000280787 7001_ $$aFrantz, Noah$$b19
000280787 7001_ $$aSonner, Jana K$$b20
000280787 7001_ $$aGrosshans, Henrike K$$b21
000280787 7001_ $$aMiguela, Albert$$b22
000280787 7001_ $$aBauer, Simone$$b23
000280787 7001_ $$aMeurs, Nina$$b24
000280787 7001_ $$aMüller, Anke$$b25
000280787 7001_ $$aBinkle-Ladisch, Lars$$b26
000280787 7001_ $$aSalinas, Gabriela$$b27
000280787 7001_ $$aJänsch, Lothar$$b28
000280787 7001_ $$aDieterich, Daniela C$$b29
000280787 7001_ $$aRiedner, Maria$$b30
000280787 7001_ $$aKrüger, Elke$$b31
000280787 7001_ $$0P:(DE-2719)2812386$$aHeppner, Frank L$$b32$$udzne
000280787 7001_ $$aGlatzel, Markus$$b33
000280787 7001_ $$aPuelles, Victor G$$b34
000280787 7001_ $$aEngler, Jan Broder$$b35
000280787 7001_ $$aNyengaard, Jens Randel$$b36
000280787 7001_ $$0P:(DE-2719)2810727$$aMisgeld, Thomas$$b37$$udzne
000280787 7001_ $$aKerschensteiner, Martin$$b38
000280787 7001_ $$aMerkler, Doron$$b39
000280787 7001_ $$aMeyer-Schwesinger, Catherine$$b40
000280787 7001_ $$aFriese, Manuel A$$b41
000280787 773__ $$0PERI:(DE-600)2001951-8$$a10.1016/j.cell.2025.05.029$$gVol. 188, no. 17, p. 4567 - 4585.e32$$n17$$p4567 - 4585.e32$$tCell$$v188$$x0092-8674$$y2025
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