Huntington's disease (HD) inclusions are stained with anti-
ubiquitin and anti-
proteasome antibodies. This, together with
proteasome activity studies on transfected cells, suggest that an impairment of the
ubiquitin-
proteasome system (UPS) may be key in HD pathogenesis. To test whether
proteasome activity is impaired in vivo, we performed enzymatic assays for the three
peptidase activities of the
proteasome in brain extracts from the HD94 conditional mouse model of HD. We found no inhibition of any of the activities, suggesting that if UPS impairment happens in vivo, it is not at the level of the
proteasome catalytic core. Intriguingly, the
chymotrypsin- and
trypsin-like activities increased selectively in the affected and aggregate-containing regions: cortex and striatum. Western blot analysis revealed no difference in total
proteasome content whereas an increase in the
interferon-inducible subunits of the immunoproteasome, LMP2 and LMP7, was observed. These subunits confer to the
proteasome catalytic properties that are optimal for
MHC-I peptide presentation. Immunohistochemistry in control mouse brain revealed LMP2 and LMP7 mainly in neurons. Accordingly, their increase in HD94 mice predominantly took place in neurons, and 5% of the
ubiquitin-positive cortical aggregates were also LMP2-positive. Ultrastructural analysis of neurons with high level of immunoproteasome subunits revealed signs of neurodegeneration like nuclear indentation or fragmentation and dark cell appearance. The neuronal induction of LMP2 and LMP7 and the associated signs of neurodegeneration were also found in HD postmortem brains. Our results indicate that LMP2 and LMP7 participate in normal neuronal physiology and suggest a role in HD neurodegeneration.