mHTT Seeding Activity: A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease

Research output: Contribution to journalArticle

Abstract

Self-propagating, amyloidogenic mutant huntingtin (mHTT) aggregates may drive progression of Huntington's disease (HD). Here, we report the development of a FRET-based mHTT aggregate seeding (FRASE) assay that enables the quantification of mHTT seeding activity (HSA) in complex biosamples from HD patients and disease models. Application of the FRASE assay revealed HSA in brain homogenates of presymptomatic HD transgenic and knockin mice and its progressive increase with phenotypic changes, suggesting that HSA quantitatively tracks disease progression. Biochemical investigations of mouse brain homogenates demonstrated that small, rather than large, mHTT structures are responsible for the HSA measured in FRASE assays. Finally, we assessed the neurotoxicity of mHTT seeds in an inducible Drosophila model transgenic for HTTex1. We found a strong correlation between the HSA measured in adult neurons and the increased mortality of transgenic HD flies, indicating that FRASE assays detect disease-relevant, neurotoxic, mHTT structures with severe phenotypic consequences in vivo. Ast et al. present the development of a FRET-based aggregate seeding (FRASE) assay that facilitates the detection and quantification of mHTT seeding activity (HSA) in complex biosamples. They show that HSA is detectable in brains of presymptomatic Huntington's disease (HD) mice and correlates with disease progression and neurotoxicity in HD transgenic flies.

Details

Authors
  • Anne Ast
  • Alexander Buntru
  • Franziska Schindler
  • Regine Hasenkopf
  • Aline Schulz
  • Lydia Brusendorf
  • Konrad Klockmeier
  • Gerlinde Grelle
  • Benjamin McMahon
  • Hannah Niederlechner
  • Isabelle Jansen
  • Lisa Diez
  • Juliane Edel
  • Annett Boeddrich
  • Sophie A. Franklin
  • Sigrid Schnoegl
  • Severine Kunz
  • Bettina Purfürst
  • Annette Gaertner
  • Harm H. Kampinga
  • A. Jennifer Morton
  • Janine Kirstein
  • Gillian P. Bates
  • Erich E. Wanker
Organisations
External organisations
  • Max Delbrück Center for Molecular Medicine (MDC)
  • Berlin Institute of Health (BIH)
  • University College London
  • University Medical Center Groningen
  • University of Cambridge
  • Leibniz-Institute for Molecular Pharmacology (FMP)
  • Evotec AG
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • disease marker, Drosophila, FRASE assay, HSA, huntingtin, Huntington's disease, mutant HTT seeding, proteotoxicity, seeding activity, self-propagation
Original languageEnglish
Pages (from-to)675-688.e6
JournalMolecular Cell
Volume71
Issue number5
Publication statusPublished - 2018 Sep 6
Publication categoryResearch
Peer-reviewedYes