Acute polyglutamine expression in inducible mouse model unravels ubiquitin/proteasome system impairment and permanent recovery attributable to aggregate formation.
The presence of intracellular ubiquitylated inclusions in neurodegenerative disorders and the role of the ubiquitin/proteasome system (UPS) in degrading abnormal hazardous proteins have given rise to the hypothesis that UPS-impairment underlies neurodegenerative processes. However, this remains controversial for polyglutamine disorders such as Huntington disease (HD). Whereas studies in cellular models have provided evidence in favor of UPS-impairment attributable to expression of the N-terminal fragment of mutant huntingtin (N-mutHtt), similar studies on mouse models failed to do so. Furthermore, we have recently shown that the increase in polyubiquitin conjugates reported in the brain of N-mutHtt mice occurs in the absence of a general UPS-impairment. In the present study we aim to clarify the potential of N-mutHtt to impair UPS function in vivo as well as the mechanisms by which neurons may adapt after prolonged exposure to N-mutHtt in genetic models. By combining UPS reporter mice with an inducible mouse model of HD, we demonstrate for the first time polyglutamine-induced global UPS-impairment in vivo. UPS-impairment occurred transiently after acute N-mutHtt expression and restoration correlated with appearance of inclusion bodies (IBs). Consistently, UPS recovery did not take place when IB formation was prevented through administration of N-mutHtt aggregation-inhibitors in both cellular and animal models. Finally, no UPS-impairment was detected in old mice constitutively expressing N-mutHtt despite the age-associated decrease in brain proteasome activity. Therefore, our data reconcile previous contradictory reports by showing that N-mutHtt can indeed impair UPS function in vivo and that N-mutHtt aggregation leads to long lasting restoration of UPS function.
Ortega
Zaira
Z
Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autonoma de Madrid and CiberNed, Madrid, Spain.
Díaz-Hernández
Miguel
M
Maynard
Christa J
CJ
Hernández
Félix
F
Dantuma
Nico P
NP
Lucas
José J
JJ
D000818:Animals; D002449:Cell Aggregation / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors; D013997:Time Factors; D025801:Ubiquitin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D010455:Peptides; D061988:Proteasome Inhibitors; D025801:Ubiquitin; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex