Special LMNN Seminar - Self-propagating huntingtin aggregates and their potential role in Huntington’s disease

Self-propagation of amyloidogenic protein aggregates may drive the progression of neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). We recently developed 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 detectable in soluble protein fractions that contain small mHTT fibrils. Furthermore, studies in an inducible Drosophila fly model revealed that the short-time production of seeding-competent mHTTex1 aggregates in fly brains is sufficient to reduce their lifespan, suggesting that mutant HTTex1 seeds are highly toxic structures. Together, our results support the hypothesis that self-propagating mHTT seeds play a critical role in HD.