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

Ast, A., Buntru, A., Schindler, F., Hasenkopf, R., Schulz, A., Brusendorf, L., Klockmeier, K., Grelle, G., McMahon, B., Niederlechner, H., Jansen, I., Diez, L., Edel, J., Boeddrich, A., Franklin, S. A., Baldo, B., Schnoegl, S., Kunz, S., Purfuerst, B., Gaertner, A., Kampinga, H. H., Morton, A. J., Petersen, A., Kirstein, J., Bates, G. P. & Wanker, E. E., 6-Sep-2018, In : Molecular Cell. 71, 5, p. 675-688.e6 21 p.

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

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DOI

  • 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
  • Barbara Baldo
  • Sigrid Schnoegl
  • Severine Kunz
  • Bettina Purfuerst
  • Annette Gaertner
  • Harm H. Kampinga
  • A. Jennifer Morton
  • Asa Petersen
  • Janine Kirstein
  • Gillian P. Bates
  • Erich E. Wanker

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.

Original languageEnglish
Pages (from-to)675-688.e6
Number of pages21
JournalMolecular Cell
Volume71
Issue number5
Publication statusPublished - 6-Sep-2018

    Keywords

  • NEURONAL INTRANUCLEAR INCLUSIONS, IN MOUSE MODEL, MUTANT HUNTINGTIN, NEURODEGENERATIVE DISEASES, ALPHA-SYNUCLEIN, CYCLIC AMPLIFICATION, CEREBROSPINAL-FLUID, ALZHEIMERS-DISEASE, TRANSGENIC MICE, EXON-1 PROTEIN

ID: 65586459