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The Journal of Neuroscience, December 17, 2003, 23(37):11653-11661

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Cellular/Molecular
Neuronal Induction of the Immunoproteasome in Huntington's Disease

Miguel Díaz-Hernández,^1 * Félix Hernández,^1 * Ester Martín-Aparicio,¹ Pilar Gómez-Ramos,² María A. Morán,² José G. Castaño,³ Isidro Ferrer,⁴ Jesús Avila,¹ and José J. Lucas¹

¹Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Contoblanco, 28049 Madrid, Spain, ²Departamento de Morfología, Facultad de Medicina, UAM, 28029 Madrid, Spain, ³Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC/UAM and Departamento de Bioquímica, Facultad de Medicina, UAM, 28029 Madrid, Spain, and ⁴Institut de Neuropatologia, Servei d'Anatomia Patologica, Hospital Princeps d'Espanya, Hospitalet de Llobregat, 08907 Barcelona, Spain

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.

Key words: Huntington's disease; proteasome activity; immunoproteasome inducible subunits: LMP2, LMP7; conditional transgenic mouse model; HD postmortem brain

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Received June 18, 2003; revised September 25, 2003; accepted October 22, 2003.

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