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mHTT seeding activity: a marker of disease progression and neurotoxicity in models of Huntington's disease

Item Type:Article
Title:mHTT seeding activity: a marker of disease progression and neurotoxicity in models of Huntington's disease
Creators Name:Ast, A. and Buntru, A. and Schindler, F. and Hasenkopf, R. and Schulz, A. and Brusendorf, L. and Klockmeier, K. and Grelle, G. and McMahon, B. and Niederlechner, H. and Jansen, I. and Diez, L. and Edel, J. and Boeddrich, A. and Franklin, S.A. and Baldo, B. and Schnoegl, S. and Kunz, S. and Purfürst, B. and Gaertner, A. and Kampinga, H.H. and Morton, A.J. and Petersén, Å. and Kirstein, J. and Bates, G.P. and Wanker, E.E.
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.
Keywords:Huntington's Disease, FRASE Assay, Mutant HTT Seeding, Huntingtin, Proteotoxicity, Seeding Activity, Disease Marker, Self-Propagation, HSA, Animals, Caenorhabditis elegans, Drosophila, Mice
Source:Molecular Cell
Publisher:Elsevier / Cell Press (U.S.A.)
Page Range:675-688
Date:6 September 2018
Official Publication:https://doi.org/10.1016/j.molcel.2018.07.032
PubMed:View item in PubMed

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