Role of GSK-3 in Huntington’s diseases

Abnormal activity of Glycogen Synthase Kinase-3 (GSK-3), a validated drug discovery target, has been implicated in the pathogenesis of several human diseases, including metabolic and neurodegenerative disorders. Recently we showed that GSK-3 impairs cellular clearance through the autophagy-lysosome pathway, a process known to be vital to neurons viability and intact function.

In Huntington’s disease (HD), expression of the mutant huntingtin protein (mHtt) leads to the formation of mHtt protein aggregates, resulting in improper function of neurons and toxic effects. Disposal of mHtt aggregates via the autophagy-lysosome network can thus be a therapeutic approach. Therefore, GSK-3 may be an important player in manipulating mHtt aggregates and its respective toxic effects in HD.

In this study, we investigated the role of GSK-3 in modulating mHtt- protein aggregation, accumulation, and induced-toxicity. We established a cell model that express GFP tagged mHtt (GFP-mHtt) and monitored GSK-3 impact of mHtt dynamics. While overexpression of GSK-3 accelerated the formation and accumulation of mHtt aggregates, enhanced autophagic activity, or, treatment with our novel GSK-3 inhibitor L807mts, significantly reduced mHtt aggregates accumulation. We further show that GSK-3 inhibition is tightly correlates with enhanced autophagy-lysosomal activity and reduction in mHtt aggregation. Preliminary work with the R6/2 HD mouse model indeed showed that treatment with L807mts lowered mHtt aggregates in the brain and improved coordination and motor activity in the treated mice. Altogether, we suggest that GSK-3 is an important player in regulating mHtt dynamics, and that the use of potent GSK-3 inhibition is a promising approach for treating HD.