Takin’ Out the Trash for Brain Health!

Immunoproteasome Deficiency Results in Age-Dependent Development of Epilepsy Leister H, Krause FF, Gil B, Prus R, Prus I, Hellhund-Zingel A, Mitra M, Da Rosa Gerbatin R, Delanty N, Beausang A, Brett FM, Farrell MA, Cryan J, O’Brien DF, Henshall DC, Helmprobst F, Pagenstecher A, Steinhoff U, Visekruna A, Engel T. Brain Commun . 2024;6(1):fcae017. doi: 10.1093/braincomms/fcae017 . eCollection 2024. PMID: 38317856 The immunoproteasome is a central protease complex required for optimal antigen presentation. Immunoproteasome activity is also associated with facilitating the degradation of misfolded and oxidized proteins, which prevents cellular stress. While extensively studied during diseases with increasing evidence suggesting a role for the immunoproteasome during pathological conditions including neurodegenerative diseases, this enzyme complex is believed to be mainly not expressed in the healthy brain. In this study, we show an age-dependent increase in polyubiquitination in the brains of wild-type mice, accompanied by an induction of immunoproteasomes, which was most prominent in neurons and microglia. In contrast, mice completely lacking immunoproteasomes (triple-knockout mice) displayed a strong increase in polyubiquitinated proteins already in the young brain and developed spontaneous epileptic seizures, beginning at the age of 6 months. Injections of kainic acid led to high epilepsy-related mortality of aged triple-knockout mice, confirming increased pathological hyperexcitability states. Notably, the expression of the immunoproteasome was reduced in the brains of patients suffering from epilepsy. In addition, the aged triple-knockout mice showed increased anxiety, tau hyperphosphorylation and degeneration of Purkinje cell population with the resulting ataxic symptoms and locomotion alterations. Collectively, our study suggests a critical role for the immunoproteasome in the maintenance of a healthy brain during ageing.