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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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; Purfürst, Bettina; Gaertner, Annette; Kampinga, Harm H.; Morton, A. Jennifer; Petersén, Åsa; Kirstein, Janine; Bates, Gillian P.; Wanker, Erich E.

I: Molecular Cell, Vol. 71, Nr. 5, 06.09.2018, s. 675-688.e6.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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, Purfürst, B, Gaertner, A, Kampinga, HH, Morton, AJ, Petersén, Å, 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, nr. 5, s. 675-688.e6. https://doi.org/10.1016/j.molcel.2018.07.032

APA

Ast, A., Buntru, A., Schindler, F., Hasenkopf, R., Schulz, A., Brusendorf, L., ... 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

CBE

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, Purfürst B, Gaertner A, Kampinga HH, Morton AJ, Petersén Å, 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. 71(5):675-688.e6. https://doi.org/10.1016/j.molcel.2018.07.032

MLA

Vancouver

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 ; Purfürst, Bettina ; Gaertner, Annette ; Kampinga, Harm H. ; Morton, A. Jennifer ; Petersén, Åsa ; Kirstein, Janine ; Bates, Gillian P. ; Wanker, Erich E. / mHTT Seeding Activity : A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease. I: Molecular Cell. 2018 ; Vol. 71, Nr. 5. s. 675-688.e6.

RIS

TY - JOUR

T1 - mHTT Seeding Activity

T2 - Molecular Cell

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 - Purfürst, Bettina

AU - Gaertner, Annette

AU - Kampinga, Harm H.

AU - Morton, A. Jennifer

AU - Petersén, Åsa

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. 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.

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. 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.

KW - disease marker

KW - Drosophila

KW - FRASE assay

KW - HSA

KW - huntingtin

KW - Huntington's disease

KW - mutant HTT seeding

KW - proteotoxicity

KW - seeding activity

KW - self-propagation

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 - 1097-4164

IS - 5

ER -