- Tan, Z
- Dai, W
- Van Erp, TGM
- Overman, J
- Demuro, A
- Digman, MA
- Hatami, A
- Albay, R
- Sontag, EM
- Potkin, KT
- Ling, S
- Macciardi, F
- Bunney, WE
- Long, JD
- Paulsen, JS
- Ringman, JM
- Parker, I
- Glabe, C
- Thompson, LM
- Chiu, W
- Potkin, SG
- et al.
© 2015 Macmillan Publishers Limited Molecular Psychiatry. 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.