Glycogen synthase kinase 3 beta suppresses accumulation of polyglutamine aggregates by inhibiting vaccinia – related kinase 2 kinase activity

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by abnormal expansion of polyglutamine repeats in N-terminal of huntingtin (1993). The level of aggregate-prone protein is controlled by a diversity of mechanisms, including molecular chaperones. It was reported that eukaryotic chaperonin CCT (also known as TRiC) attenuates the accumulation of huntingtin (Htt)-polyQ proteins aggregation and cytotoxicity (Kitamura, Kubota et al., 2006). Vaccinia-related kinase2 (VRK2) is Ser/Thr kinase that negatively regulates TRiC. VRK2-mediated degradation of TRiC increases polyglutamine protein aggregation involved in HD (Kim, Park et al., 2014). Here we found that Glycogen synthase kinase 3 beta (GSK3β) directly binds to VRK2 and inhibits VRK2 kinase activity. Remarkably, GSK3β inhibits degradation of TRiC protein levels by inhibition of VRK2 kinase activity and the formation of HttQ103-GFP aggregates was decreased by GSK3β. Thus, our findings elucidate the HD molecular mechanism underlying GSK3β signaling and suggest targets for further therapeutic trials in HD.