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

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title = "mHTT Seeding Activity: A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease",
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. 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.",
keywords = "disease marker, Drosophila, FRASE assay, HSA, huntingtin, Huntington's disease, mutant HTT seeding, proteotoxicity, seeding activity, self-propagation",
author = "Anne Ast and Alexander Buntru and Franziska Schindler and Regine Hasenkopf and Aline Schulz and Lydia Brusendorf and Konrad Klockmeier and Gerlinde Grelle and Benjamin McMahon and Hannah Niederlechner and Isabelle Jansen and Lisa Diez and Juliane Edel and Annett Boeddrich and Franklin, {Sophie A.} and Barbara Baldo and Sigrid Schnoegl and Severine Kunz and Bettina Purf{\"u}rst and Annette Gaertner and Kampinga, {Harm H.} and Morton, {A. Jennifer} and {\AA}sa Peters{\'e}n and Janine Kirstein and Bates, {Gillian P.} and Wanker, {Erich E.}",
year = "2018",
month = "9",
day = "6",
doi = "10.1016/j.molcel.2018.07.032",
language = "English",
volume = "71",
pages = "675--688.e6",
journal = "Molecular Cell",
issn = "1097-4164",
publisher = "Cell Press",
number = "5",