Non-neuronal induction of immunoproteasome subunits in an ALS model: possible mediation by cytokines

Exp Neurol. 2005 Dec;196(2):441-51. doi: 10.1016/j.expneurol.2005.08.027. Epub 2005 Oct 19.


Protein aggregation is a pathologic hallmark of familial amyotrophic lateral sclerosis caused by mutations in the Cu, Zn superoxide dismutase gene. Although SOD1-positive aggregates can be cleared by proteasomes, aggregates have been hypothesized to interfere with proteasome activity, leading to a vicious cycle that further enhances aggregate accumulation. To address this issue, we measured proteasome activity in transgenic mice expressing a G93A SOD1 mutation. We find that proteasome activity is induced in the spinal cord of such mice compared to controls but is not altered in uninvolved organs such as liver or spleen. This induction within spinal cord is not related to an overall increase in the total number of proteasome subunits, as evidenced by the steady expression levels of constitutive alpha7 and beta5 subunits. In contrast, we found a marked increase of inducible beta proteasome subunits, LMP2, MECL-1 and LMP7. This induction of immunoproteasome subunits does not occur in all spinal cord cell types but appears limited to astrocytes and microglia. The induction of immunoproteasome subunits in G93A spinal cord organotypic slices treated with TNF-alpha and interferon-gamma suggest that certain cytokines may mediate such responses in vivo. Our results indicate that there is an overall increase in proteasome function in the spinal cords of G93A SOD1 mice that correlates with an induction of immunoproteasomes subunits and a shift toward immunoproteasome composition. These results suggest that increased, rather than decreased, proteasome function is a response of certain cell types to mutant SOD1-induced disease within spinal cord.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Blotting, Western / methods
  • Cytokines / pharmacology*
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Humans
  • Immunohistochemistry / methods
  • In Vitro Techniques
  • Mice
  • Mice, Transgenic
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Subunits / metabolism
  • Spinal Cord / drug effects*
  • Spinal Cord / metabolism
  • Spinal Cord / physiopathology
  • Superoxide Dismutase / genetics


  • Cytokines
  • Protein Subunits
  • SOD1 G93A protein
  • Superoxide Dismutase
  • Proteasome Endopeptidase Complex