Journal
MOLECULAR CELL
Volume 71, Issue 5, Pages 675-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.07.032
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Funding
- UK Medical Research Council [G0400074]
- Brains for Dementia Research
- HDSA
- Swedish Research Council
- CHDI Foundation
- EC funding initiative ERA-NET NEURON, consortium ABETA ID - German Federal Ministry for Education and Research (BMBF) [01W1301]
- Berlin Institute of Health Collaborative Research - German Federal Ministry for Education and Research (BMBF) [1.1.2.a.3]
- Helmholtz Validation Fund - Helmholtz Association, Germany [HVF-0013]
- Stiftung Charite
- Max Delbruck Center for Molecular Medicine in the Helmholtz Association for application-oriented research
- MRC [UKDRI-1008/1, G0400074] Funding Source: UKRI
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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.
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