Abstract

Self-propagation of amyloidogenic protein aggregates may drive the progression of neurodegenerative diseases including Huntington’s disease (HD). We recently developed of a cell-free, FRET -based mutant huntingtin (mHTT) aggregate seeding (FRASE) biosensor assay that enables the detection and quantification of mHTT seeding activity (HSA) in complex biosamples from HD patients and disease models. Application of FRASE assays revealed HSA in crude brain homogenates of presymptomatic HD transgenic mice and its progressive increase with development of the phenotype, indicating that HSA quantitatively tracks disease progression. Biochemical investigations of mouse brain homogenates demonstrated that HSA is predominantly detectable in soluble protein fractions, which contain small, fibrillar mHTT oligomers. Finally, we assessed the disease relevance of mHTT exon-1 (mHTTex1) seeds in an inducible Drosophila fly model. We demonstrated that the short-time production of seeding-competent mHTTex1 aggregates in fly brains leads to a dramatically reduced lifespan, suggesting that mutant HTTex1 seeds are highly toxic structures. Together, our results suggest a central role of self-propagating mHTT seeds in the development and progression of HD.