Original Item ID
Huntington’s disease (HD), a progressive neurodegenerative disease, is caused by an expanded CAG triplet repeat producing a mutant huntingtin protein (mHTT) with a polyglutamine-repeat expansion. Onset of symptoms in mutant huntingtin gene-carrying individuals remains unpredictable. We report that synthetic polyglutamine oligomers and cerebrospinal fluid (CSF) from BACHD transgenic rats and from human HD subjects can seed mutant huntingtin aggregation in a cell model and its cell lysate. Our studies demonstrate that seeding requires the mutant huntingtin template and may reflect an underlying prion-like protein propagation mechanism. Light and cryo-electron microscopy show that synthetic seeds nucleate and enhance mutant huntingtin aggregation. This seeding assay distinguishes HD subjects from healthy and non-HD dementia controls without overlap (blinded samples). Ultimately, this seeding property in HD patient CSF may form the basis of a molecular biomarker assay to monitor HD and evaluate therapies that target mHTT.
Tan, Z.; Dai, W.; van Erp, Theo G.M.; Overman, J.; Demuro, A.; Digman, M. A.; Hatami, A.; Albay, R.; Sontag, Emily M.; Potkin, K. T.; Ling, S.; Macciardi, F.; Bunney, W. E.; Long, J. D.; Paulsen, J. S.; Ringman, J. M.; Parker, I.; Glabe, Charles G.; Thompson, L. M.; Chiu, W.; and Potkin, Steven G., "Huntington’s Disease Cerebrospinal Fluid Seeds Aggregation of Mutant Huntingtin" (2015). Biological Sciences Faculty Research and Publications. 939.
ADA Accessible Version