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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; ... Wanker, EE; + view all (2018) mHTT Seeding Activity: A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease. Molecular Cell , 71 (5) pp. 675-688. 10.1016/j.molcel.2018.07.032. Green open access

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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.

Type: Article
Title: mHTT Seeding Activity: A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.molcel.2018.07.032
Publisher version: https://doi.org/10.1016/j.molcel.2018.07.032
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Huntington’s disease, FRASE assay, mutant HTT seeding, huntingtin, Drosophila, proteotoxicity, seeding activity, disease marker, self-propagation, HSA
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10058308
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