Seminar

Ubiquitin-proteasome system and ER-stress in Huntington's disease and epilepsy

José Javier Lucas, PhD

The presence of ubiquitylated inclusions in neurodegenerative disorders and the role of the ubiquitin/proteasome system (UPS) in degrading abnormal hazardous proteins gave rise to the hypothesis that UPS-impairment underlies neurodegeneration. Similarly, the unfolded protein response (UPR) that takes place when the capacity of endoplasmic reticulum (ER) to handle improperly folded proteins is exceeded has also been suggested to contribute to neurodegeneration either by defect or excessive execution. Regarding the UPS, deficient function is believed to contribute to Parkinson’s disease, amyotrophic lateral sclerosis and prion diseases. However, this hypothesis has remained controversial for polyglutamine disorders such as Huntington’s disease (HD). Whereas studies in cellular models provided evidence in favor of UPS-impairment due to expression of the N-terminal fragment of mutant huntingtin (N-mutHtt), similar studies on mouse models systematically failed to do so. By analyzing UPS reporter mice combined with our inducible N-term-mutHtt HD-mouse model, we were recently able to detect for the first time polyglutamine-induced UPS impairment in vivo. However, this UPS impairment occurred only transiently upon acute N-mutHtt expression and restoration correlated with appearance of inclusion bodies (IBs). Consistently, UPS did not recover if IB formation was prevented by administering N-mutHtt aggregation-inhibitors. 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. Regarding execution of the ER stress response in HD, we recently reported defective processing of ATF6α to its active nuclear form in both animal models and HD patients. This decrease in ATF6α processing is accompanied by a decrease in the accumulation of the small GTPase Rheb (Ras-homologue enriched in brain) and accumulation of cell cycle re-entry markers in post-mitotic neurons. We are currently studying additional features of altered ER stress execution in HD and in epilepsy-induced neurodegeneration. We are also exploring the therapeutic potential of drugs that contribute to normalize the ER stress response in mouse models.