Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: Implications for Huntington's disease therapy

The accumulation of insoluble protein aggregates in intra and perinuclear i nclusions is a hallmark of Huntington's disease (HD) and related glutamine- repeat disorders. A central question is whether protein aggregation plays a direct role in the pathogenesis of these neurodegenerative diseases. Here we show by using a filter retardation assay that the mAb 1C2. which specifi cally recognizes the elongated polyglutamine (polyQ) stretch in huntingtin, and the chemical compounds Congo red, thioflavine S. chrysamine G, and Dir ect fast yellow inhibit HD exon 1 protein aggregation in a dose-dependent m anner. On the other hand. potential inhibitors of amyloid-beta formation su ch as thioflavine T. gossypol, melatonin, and rifampicin had little or no i nhibitory effect on huntingtin aggregation in vitro. The results obtained b y the filtration assay were confirmed by electron microscopy, SDS/ PAGE, an d MS. Furthermore. cell culture studies revealed that the Congo red dye at micromolar concentrations reduced the extent of HD exon 1 aggregation in tr ansiently transfected COS cells. Together, these findings contribute to a b etter understanding of the mechanism of huntingtin fibrillogenesis in vitro and provide the basis for the development of new huntingtin aggregation in hibitors that may be effective in treating HD.