Publication

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., Grelle, G., McMahon, B., Niederlechner, H., Jansen, I., Diez, L., Edel, J., Boeddrich, A., Franklin, S. A., Baldo, B., Schnoegl, S., Kunz, S., Purfuerst, B., Gaertner, A., Kampinga, H. H., Morton, A. J., Petersen, A., Kirstein, J., Bates, G. P. & Wanker, E. E., 6-Sep-2018, In : Molecular Cell. 71, 5, p. 675-688.e6 21 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Ast, A., Buntru, A., Schindler, F., Hasenkopf, R., Schulz, A., Brusendorf, L., Klockmeier, K., Grelle, G., McMahon, B., Niederlechner, H., Jansen, I., Diez, L., Edel, J., Boeddrich, A., Franklin, S. A., Baldo, B., Schnoegl, S., Kunz, S., Purfuerst, B., ... Wanker, E. E. (2018). mHTT Seeding Activity: A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease. Molecular Cell, 71(5), 675-688.e6. https://doi.org/10.1016/j.molcel.2018.07.032

Author

Ast, Anne ; Buntru, Alexander ; Schindler, Franziska ; Hasenkopf, Regine ; Schulz, Aline ; Brusendorf, Lydia ; Klockmeier, Konrad ; Grelle, Gerlinde ; McMahon, Benjamin ; Niederlechner, Hannah ; Jansen, Isabelle ; Diez, Lisa ; Edel, Juliane ; Boeddrich, Annett ; Franklin, Sophie A. ; Baldo, Barbara ; Schnoegl, Sigrid ; Kunz, Severine ; Purfuerst, Bettina ; Gaertner, Annette ; Kampinga, Harm H. ; Morton, A. Jennifer ; Petersen, Asa ; Kirstein, Janine ; Bates, Gillian P. ; Wanker, Erich E. / mHTT Seeding Activity : A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease. In: Molecular Cell. 2018 ; Vol. 71, No. 5. pp. 675-688.e6.

Harvard

Ast, A, Buntru, A, Schindler, F, Hasenkopf, R, Schulz, A, Brusendorf, L, Klockmeier, K, Grelle, G, McMahon, B, Niederlechner, H, Jansen, I, Diez, L, Edel, J, Boeddrich, A, Franklin, SA, Baldo, B, Schnoegl, S, Kunz, S, Purfuerst, B, Gaertner, A, Kampinga, HH, Morton, AJ, Petersen, A, Kirstein, J, Bates, GP & Wanker, EE 2018, 'mHTT Seeding Activity: A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease', Molecular Cell, vol. 71, no. 5, pp. 675-688.e6. https://doi.org/10.1016/j.molcel.2018.07.032

Standard

mHTT Seeding Activity : A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease. / Ast, Anne; Buntru, Alexander; Schindler, Franziska; Hasenkopf, Regine; Schulz, Aline; Brusendorf, Lydia; Klockmeier, Konrad; Grelle, Gerlinde; McMahon, Benjamin; Niederlechner, Hannah; Jansen, Isabelle; Diez, Lisa; Edel, Juliane; Boeddrich, Annett; Franklin, Sophie A.; Baldo, Barbara; Schnoegl, Sigrid; Kunz, Severine; Purfuerst, Bettina; Gaertner, Annette; Kampinga, Harm H.; Morton, A. Jennifer; Petersen, Asa; Kirstein, Janine; Bates, Gillian P.; Wanker, Erich E.

In: Molecular Cell, Vol. 71, No. 5, 06.09.2018, p. 675-688.e6.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Ast A, Buntru A, Schindler F, Hasenkopf R, Schulz A, Brusendorf L et al. mHTT Seeding Activity: A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease. Molecular Cell. 2018 Sep 6;71(5):675-688.e6. https://doi.org/10.1016/j.molcel.2018.07.032


BibTeX

@article{6b5f7fa4969c4d6fb90f087cdb769386,
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.",
keywords = "NEURONAL INTRANUCLEAR INCLUSIONS, IN MOUSE MODEL, MUTANT HUNTINGTIN, NEURODEGENERATIVE DISEASES, ALPHA-SYNUCLEIN, CYCLIC AMPLIFICATION, CEREBROSPINAL-FLUID, ALZHEIMERS-DISEASE, TRANSGENIC MICE, EXON-1 PROTEIN",
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 Purfuerst and Annette Gaertner and Kampinga, {Harm H.} and Morton, {A. Jennifer} and Asa Petersen and Janine Kirstein and Bates, {Gillian P.} and Wanker, {Erich E.}",
year = "2018",
month = sep,
day = "6",
doi = "10.1016/j.molcel.2018.07.032",
language = "English",
volume = "71",
pages = "675--688.e6",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "CELL PRESS",
number = "5",

}

RIS

TY - JOUR

T1 - mHTT Seeding Activity

T2 - A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease

AU - Ast, Anne

AU - Buntru, Alexander

AU - Schindler, Franziska

AU - Hasenkopf, Regine

AU - Schulz, Aline

AU - Brusendorf, Lydia

AU - Klockmeier, Konrad

AU - Grelle, Gerlinde

AU - McMahon, Benjamin

AU - Niederlechner, Hannah

AU - Jansen, Isabelle

AU - Diez, Lisa

AU - Edel, Juliane

AU - Boeddrich, Annett

AU - Franklin, Sophie A.

AU - Baldo, Barbara

AU - Schnoegl, Sigrid

AU - Kunz, Severine

AU - Purfuerst, Bettina

AU - Gaertner, Annette

AU - Kampinga, Harm H.

AU - Morton, A. Jennifer

AU - Petersen, Asa

AU - Kirstein, Janine

AU - Bates, Gillian P.

AU - Wanker, Erich E.

PY - 2018/9/6

Y1 - 2018/9/6

N2 - 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.

AB - 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.

KW - NEURONAL INTRANUCLEAR INCLUSIONS

KW - IN MOUSE MODEL

KW - MUTANT HUNTINGTIN

KW - NEURODEGENERATIVE DISEASES

KW - ALPHA-SYNUCLEIN

KW - CYCLIC AMPLIFICATION

KW - CEREBROSPINAL-FLUID

KW - ALZHEIMERS-DISEASE

KW - TRANSGENIC MICE

KW - EXON-1 PROTEIN

U2 - 10.1016/j.molcel.2018.07.032

DO - 10.1016/j.molcel.2018.07.032

M3 - Article

VL - 71

SP - 675-688.e6

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 5

ER -

ID: 65586459