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Immunoproteasome deficiency results in age-dependent development of epilepsy.pdf (1.18 MB)

Immunoproteasome deficiency results in age-dependent development of epilepsy

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journal contribution
posted on 2024-03-19, 13:21 authored by Hanna Leister, Felix F Krause, Beatriz Gil, Ruslan Prus, Inna Prus, Anne Hellhund-Zingel, Meghma Mitra, Rogerio Da Rosa Gerbatin, Norman DelantyNorman Delanty, Alan Beausang, Francesca BrettFrancesca Brett, Michael A Farrell, Jane CryanJane Cryan, Donncha O'BrienDonncha O'Brien, David HenshallDavid Henshall, Frederik Helmprobst, Axel Pagenstecher, Ulrich Steinhoff, Alexander Visekruna, Tobias EngelTobias Engel

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. 

Funding

Science Foundation Ireland (17/CDA/4708)

European Regional Development Fund

FutureNeuro industry partners 16/RC/3948

DGF-VI 562/10-1

FAZIT Stiftung

DRUID-LOEWE

History

Data Availability Statement

All data and materials used for this research project will be made available upon reasonable request

Comments

The original article is available at https://academic.oup.com/

Published Citation

Leister H, et al. Immunoproteasome deficiency results in age-dependent development of epilepsy. Brain Commun. 2024;6(1):fcae017.

Publication Date

29 January 2024

PubMed ID

38317856

Department/Unit

  • Physiology and Medical Physics
  • FutureNeuro Centre
  • Beaumont Hospital
  • Clinical Neurological Sciences
  • Pathology
  • Surgery
  • School of Pharmacy and Biomolecular Sciences

Publisher

Oxford University Press

Version

  • Published Version (Version of Record)