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Metabolic disruption identified in the Huntington’s disease transgenic sheep model

Huntington’s disease (HD) is a dominantly inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of HTT, encoding huntingtin. There are no therapies that can delay the progression of this devastating disease. One feature of HD that may play a critical role i...

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Autores principales: Handley, Renee. R., Reid, Suzanne J., Patassini, Stefano, Rudiger, Skye R., Obolonkin, Vladimir, McLaughlan, Clive. J., Jacobsen, Jessie C., Gusella, James F., MacDonald, Marcy E., Waldvogel, Henry J., Bawden, C. Simon, Faull, Richard L. M., Snell, Russell G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749952/
https://www.ncbi.nlm.nih.gov/pubmed/26864449
http://dx.doi.org/10.1038/srep20681
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author Handley, Renee. R.
Reid, Suzanne J.
Patassini, Stefano
Rudiger, Skye R.
Obolonkin, Vladimir
McLaughlan, Clive. J.
Jacobsen, Jessie C.
Gusella, James F.
MacDonald, Marcy E.
Waldvogel, Henry J.
Bawden, C. Simon
Faull, Richard L. M.
Snell, Russell G.
author_facet Handley, Renee. R.
Reid, Suzanne J.
Patassini, Stefano
Rudiger, Skye R.
Obolonkin, Vladimir
McLaughlan, Clive. J.
Jacobsen, Jessie C.
Gusella, James F.
MacDonald, Marcy E.
Waldvogel, Henry J.
Bawden, C. Simon
Faull, Richard L. M.
Snell, Russell G.
author_sort Handley, Renee. R.
collection PubMed
description Huntington’s disease (HD) is a dominantly inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of HTT, encoding huntingtin. There are no therapies that can delay the progression of this devastating disease. One feature of HD that may play a critical role in its pathogenesis is metabolic disruption. Consequently, we undertook a comparative study of metabolites in our transgenic sheep model of HD (OVT73). This model does not display overt symptoms of HD but has circadian rhythm alterations and molecular changes characteristic of the early phase disease. Quantitative metabolite profiles were generated from the motor cortex, hippocampus, cerebellum and liver tissue of 5 year old transgenic sheep and matched controls by gas chromatography-mass spectrometry. Differentially abundant metabolites were evident in the cerebellum and liver. There was striking tissue-specificity, with predominantly amino acids affected in the transgenic cerebellum and fatty acids in the transgenic liver, which together may indicate a hyper-metabolic state. Furthermore, there were more strong pair-wise correlations of metabolite abundance in transgenic than in wild-type cerebellum and liver, suggesting altered metabolic constraints. Together these differences indicate a metabolic disruption in the sheep model of HD and could provide insight into the presymptomatic human disease.
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spelling pubmed-47499522016-02-17 Metabolic disruption identified in the Huntington’s disease transgenic sheep model Handley, Renee. R. Reid, Suzanne J. Patassini, Stefano Rudiger, Skye R. Obolonkin, Vladimir McLaughlan, Clive. J. Jacobsen, Jessie C. Gusella, James F. MacDonald, Marcy E. Waldvogel, Henry J. Bawden, C. Simon Faull, Richard L. M. Snell, Russell G. Sci Rep Article Huntington’s disease (HD) is a dominantly inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of HTT, encoding huntingtin. There are no therapies that can delay the progression of this devastating disease. One feature of HD that may play a critical role in its pathogenesis is metabolic disruption. Consequently, we undertook a comparative study of metabolites in our transgenic sheep model of HD (OVT73). This model does not display overt symptoms of HD but has circadian rhythm alterations and molecular changes characteristic of the early phase disease. Quantitative metabolite profiles were generated from the motor cortex, hippocampus, cerebellum and liver tissue of 5 year old transgenic sheep and matched controls by gas chromatography-mass spectrometry. Differentially abundant metabolites were evident in the cerebellum and liver. There was striking tissue-specificity, with predominantly amino acids affected in the transgenic cerebellum and fatty acids in the transgenic liver, which together may indicate a hyper-metabolic state. Furthermore, there were more strong pair-wise correlations of metabolite abundance in transgenic than in wild-type cerebellum and liver, suggesting altered metabolic constraints. Together these differences indicate a metabolic disruption in the sheep model of HD and could provide insight into the presymptomatic human disease. Nature Publishing Group 2016-02-11 /pmc/articles/PMC4749952/ /pubmed/26864449 http://dx.doi.org/10.1038/srep20681 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Handley, Renee. R.
Reid, Suzanne J.
Patassini, Stefano
Rudiger, Skye R.
Obolonkin, Vladimir
McLaughlan, Clive. J.
Jacobsen, Jessie C.
Gusella, James F.
MacDonald, Marcy E.
Waldvogel, Henry J.
Bawden, C. Simon
Faull, Richard L. M.
Snell, Russell G.
Metabolic disruption identified in the Huntington’s disease transgenic sheep model
title Metabolic disruption identified in the Huntington’s disease transgenic sheep model
title_full Metabolic disruption identified in the Huntington’s disease transgenic sheep model
title_fullStr Metabolic disruption identified in the Huntington’s disease transgenic sheep model
title_full_unstemmed Metabolic disruption identified in the Huntington’s disease transgenic sheep model
title_short Metabolic disruption identified in the Huntington’s disease transgenic sheep model
title_sort metabolic disruption identified in the huntington’s disease transgenic sheep model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749952/
https://www.ncbi.nlm.nih.gov/pubmed/26864449
http://dx.doi.org/10.1038/srep20681
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