mHTT Seeding Activity : A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease
(2018) In Molecular Cell 71(5). p.6-688- 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... (More)
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. Ast et al. present the development of a FRET-based aggregate seeding (FRASE) assay that facilitates the detection and quantification of mHTT seeding activity (HSA) in complex biosamples. They show that HSA is detectable in brains of presymptomatic Huntington's disease (HD) mice and correlates with disease progression and neurotoxicity in HD transgenic flies.
(Less)
- author
- organization
- publishing date
- 2018-09-06
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- disease marker, Drosophila, FRASE assay, HSA, huntingtin, Huntington's disease, mutant HTT seeding, proteotoxicity, seeding activity, self-propagation
- in
- Molecular Cell
- volume
- 71
- issue
- 5
- pages
- 6 - 688
- publisher
- Cell Press
- external identifiers
-
- pmid:30193095
- scopus:85051681519
- ISSN
- 1097-2765
- DOI
- 10.1016/j.molcel.2018.07.032
- language
- English
- LU publication?
- yes
- id
- a46b0657-8761-4a15-bd76-43dad362a9ea
- date added to LUP
- 2018-09-13 12:46:52
- date last changed
- 2024-06-10 17:22:46
@article{a46b0657-8761-4a15-bd76-43dad362a9ea,
abstract = {{<p>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. Ast et al. present the development of a FRET-based aggregate seeding (FRASE) assay that facilitates the detection and quantification of mHTT seeding activity (HSA) in complex biosamples. They show that HSA is detectable in brains of presymptomatic Huntington's disease (HD) mice and correlates with disease progression and neurotoxicity in HD transgenic flies.</p>}},
author = {{Ast, Anne and Buntru, Alexander and Schindler, Franziska and Hasenkopf, Regine and Schulz, Aline and Brusendorf, Lydia and Klockmeier, Konrad and Grelle, Gerlinde and McMahon, Benjamin and Niederlechner, Hannah and Jansen, Isabelle and Diez, Lisa and Edel, Juliane and Boeddrich, Annett and Franklin, Sophie A. and Baldo, Barbara and Schnoegl, Sigrid and Kunz, Severine and Purfürst, Bettina and Gaertner, Annette and Kampinga, Harm H. and Morton, A. Jennifer and Petersén, Åsa and Kirstein, Janine and Bates, Gillian P. and Wanker, Erich E.}},
issn = {{1097-2765}},
keywords = {{disease marker; Drosophila; FRASE assay; HSA; huntingtin; Huntington's disease; mutant HTT seeding; proteotoxicity; seeding activity; self-propagation}},
language = {{eng}},
month = {{09}},
number = {{5}},
pages = {{6--688}},
publisher = {{Cell Press}},
series = {{Molecular Cell}},
title = {{mHTT Seeding Activity : A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease}},
url = {{http://dx.doi.org/10.1016/j.molcel.2018.07.032}},
doi = {{10.1016/j.molcel.2018.07.032}},
volume = {{71}},
year = {{2018}},
}