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Mol Cell. 2018 Sep 6;71(5):675-688.e6. doi: 10.1016/j.molcel.2018.07.032.

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

Author information

1
Neuroproteomics, Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany.
2
Huntington's Disease Centre, Department of Neurodegenerative Disease and Dementia Research Institute, UCL Institute of Neurology, London WC1N 3BG, UK.
3
Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
4
Electron Microscopy Core Facility, Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
5
Evotec AG, Manfred Eigen Campus, 22419 Hamburg, Germany.
6
Department of Cell Biology, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
7
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
8
Proteostasis in Aging and Disease, Leibniz-Institute for Molecular Pharmacology (FMP), 13125 Berlin, Germany.
9
Neuroproteomics, Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany. Electronic address: ewanker@mdc-berlin.de.

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:

Drosophila; FRASE assay; HSA; Huntington’s disease; disease marker; huntingtin; mutant HTT seeding; proteotoxicity; seeding activity; self-propagation

PMID:
30193095
DOI:
10.1016/j.molcel.2018.07.032
[Indexed for MEDLINE]
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