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

Abstract

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 UPSimpairment 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.

Genesis of ER stress in Huntington’s Disease

“…1), similar to what has been found in other neurodegenerative diseases [167]. This is consistent with increasing evidence that Htt oligomers and not aggregates are the cytotoxic species in HD [5][6][7] and the reports of UPS inhibition before Htt inclusion into large aggregates [168][169][170]. This might explain why clinical trials of anti-aggregating molecules in HD have been so far unsuccessful [171].…”

A Novel “Molecular Tweezer” Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo

“…A recent report demonstrated that overexpression of polyglutamine results in transient UPS inhibition in mice, but the activity returned when large inclusions formed [47]. Thus, amyloidogenic protein oligomers appear to act in a vicious manner akin to the human immunodeficiency virus, shutting down the very system expected to rid them.…”

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

“…Our data provide unique in vivo evidence that proteasomal insufficiency is ubiquitously encountered in various forms of inherited retinal degeneration associated with misfolding or mistargeting of both cytosolic and membrane proteins. Whereas the studies of other neurodegenerative diseases revealed a strong association between the underlying pathology and impaired proteasomal function (37)(38)(39)(40), this important stress factor largely escaped the attention of researchers studying retinitis pigmentosa and allied diseases. Given that inherited retinal disorders are typically diagnosed at their early stages, the emerging therapeutic strategies targeting proteasomes in neurodegeneration (41) could be particularly efficacious in treating these blinding conditions.…”