Structural and biochemical studies on Huntingtin protein and identification of novel therapeuti strategies for Huntington's disease

Abstract

he abnormal expansion of the poly-glutamine (polyQ) tract, which presents at the N-terminal region of huntingtin protein (HTT), causes Huntington’s disease (HD). However, the biological function of HTT and the pathogenic mechanism of disease are still unknown. Previous studies have suggested that the polyQ expansion may induce neurological disorders by affecting HTT-related cellular functions or forming toxic aggregates containing HTT N-terminal fragments. Therefore, understanding the molecular basis for the effect of polyQ expansion on HTT and figuring out how to reduce toxic HTT N-terminal fragments are essential to overcome HD. In this thesis, using integrative structural and biochemical studies, I presented molecular evidence that polyQ expansion in N-terminal HTT alters the overall structural and functional properties of HTT. In addition, I determined a novel function of HTT that induces the formation of F-actin bundle by directly binding to F-actin through the Bridge domain. Furthermore, I proposed an HTT isoform as a potential therapeutic target that preserves the structural and biophysical properties of canonical HTT and is also perfectly resistant to N-terminal cleavage by caspase-6. In conclusion, these findings have important implications for understanding the pathogenesis and providing a new therapeutic strategy for HD in the new sight.