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60th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN)

German Society for Neuropathology and Neuroanatomy

26. - 28.08.2015, Berlin

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Impact of immunoproteasomes on the pathogenesis of neurodegenerative diseases

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  • corresponding author presenting/speaker Lisa K. Wagner - Charité- Universitätsmedizin Berlin, Department of Neuropathology, Berlin, Germany
  • Kate E. Gilling - Charité - Universitätsmedizin Berlin, Institute of Biochemistry, Berlin, Germany
  • Peter M. Kloetzel - Charité - Universitätsmedizin Berlin, Institute of Biochemistry, Berlin, Germany
  • Elke Krüger - Charité - Universitätsmedizin Berlin, Institute of Biochemistry, Berlin, Germany
  • Stefan Prokop - Charité- Universitätsmedizin Berlin, Department of Neuropathology, Berlin, Germany
  • Frank L. Heppner - Charité- Universitätsmedizin Berlin, Department of Neuropathology, Berlin, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 60th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Berlin, 26.-28.08.2015. Düsseldorf: German Medical Science GMS Publishing House; 2015. Doc15dgnnP14

doi: 10.3205/15dgnn38, urn:nbn:de:0183-15dgnn383

Published: August 25, 2015

© 2015 Wagner et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

Text

The ubiquitin-proteasome-system (UPS) plays a central role in clearance of misfolded and oxidant-damaged proteins, which comprise a hallmark of many neurodegenerative diseases. Immunoproteasomes (iP) represent a specialized type of proteasomes, which is induced upon stimulation with proinflammatory cytokines. Besides their role in viral infections, iPs play an important role in clearance of oxidant-damaged proteins and determine the outcome of various pathological conditions, including CNS disorders.

Here, we demonstrate that iP subunit expression increases in the brain upon aging and is significantly accelerated in mice accumulating misfolded proteins, resembling Alzheimer's (AD) and Parkinson's disease (PD).

Genetic ablation of the LMP7 iP subunit and therefore iP activity, attenuated the secretion of proinflammatory cytokines by microglia in AD mice. Interestingly, iP deficiency revealed no major impact on extracellular cerebral beta-amyloid burden, while, PD mice lacking functional iPs exhibited increased intracellular alpha-Synuclein pathology and a worsened motoric phenotype.

Our studies show that iPs have a distinct pathogenetic impact in murine models harbouring intracellular vs. extracellular protein deposits in the CNS and highlight the potential of modulating iPs to modify the course of neurodegenerative diseases.