Acute Polyglutamine Expression in Inducible Mouse Model Unravels Ubiquitin/Proteasome System Impairment and Permanent Recovery Attributable to Aggregate Formation

• DOI: 10.1523/jneurosci.5673-09.2010
• Publication Date: 2010-03-10T19:19:37Z
• Authors: Zaira Ortega; Miguel Díaz-Herná...; Christa J. Maynard; Félix Hernández; Nico P. Dantuma; José J. Lucas
• Keywords: Cellular model; Huntingtin Protein

The presence of intracellular ubiquitylated inclusions in neurodegenerative disorders and the role ubiquitin/proteasome system (UPS) degrading abnormal hazardous proteins have given rise to hypothesis that UPS-impairment underlies processes. However, this remains controversial for polyglutamine such as Huntington disease (HD). Whereas studies cellular models provided evidence favor attributable expression N-terminal fragment mutant huntingtin (N-mutHtt), similar on mouse failed do so. Furthermore, we recently shown increase polyubiquitin conjugates reported brain N-mutHtt mice occurs absence a general UPS-impairment. In present study aim clarify potential impair UPS function vivo well mechanisms by which neurons may adapt after prolonged exposure genetic models. By combining reporter with an inducible model HD, demonstrate first time polyglutamine-induced global vivo. occurred transiently acute restoration correlated appearance inclusion bodies (IBs). Consistently, recovery did not take place when IB formation was prevented through administration aggregation-inhibitors both animal Finally, no detected old constitutively expressing despite age-associated decrease proteasome activity. Therefore, our data reconcile previous contradictory reports showing can indeed aggregation leads long lasting function.