Иммунопротеоз нарушает нейронный метаболизм и стимулирует нейродегенерацию в множестве склерозов.
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Woo Marcel S, Brand Johannes, Bal Lukas C, Moritz Manuela, Walkenhorst Mark, Vieira Vanessa, Ipenberg Inbal, Rothammer Nicola, Wang Man, Dogan Batuhan, Loreth Desirée, Mayer Christina, Nagel Darwin, Wagner Ingrid, Pfeffer Lena Kristina, Landgraf Peter, van Ham Marco, Mattern Kuno M-J, Winschel Ingo, Frantz Noah, Sonner Jana K, Grosshans Henrike K, Miguela Albert, Bauer Simone, Meurs Nina, Müller Anke, Binkle-Ladisch Lars, Salinas Gabriela, Jänsch Lothar, Dieterich Daniela C, Riedner Maria, Krüger Elke, Heppner Frank L, Glatzel Markus, Puelles Victor G, Engler Jan Broder, Nyengaard Jens Randel, Misgeld Thomas, Kerschensteiner Martin, Merkler Doron, Meyer-Schwesinger Catherine, Friese Manuel A
Аннотация
Оригинал публикации
The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis.
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.