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Open Access Publications from the University of California

Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin

  • Author(s): 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.

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