Cargando…

A transgenic minipig model of Huntington's disease shows early signs of behavioral and molecular pathologies

Huntington's disease (HD) is a monogenic, progressive, neurodegenerative disorder with currently no available treatment. The Libechov transgenic minipig model for HD (TgHD) displays neuroanatomical similarities to humans and exhibits slow disease progression, and is therefore more powerful than...

Descripción completa

Detalles Bibliográficos
Autores principales: Askeland, Georgina, Rodinova, Marie, Štufková, Hana, Dosoudilova, Zaneta, Baxa, Monika, Smatlikova, Petra, Bohuslavova, Bozena, Klempir, Jiri, Nguyen, The Duong, Kuśnierczyk, Anna, Bjørås, Magnar, Klungland, Arne, Hansikova, Hana, Ellederova, Zdenka, Eide, Lars
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215428/
https://www.ncbi.nlm.nih.gov/pubmed/30254085
http://dx.doi.org/10.1242/dmm.035949
_version_ 1783368148513193984
author Askeland, Georgina
Rodinova, Marie
Štufková, Hana
Dosoudilova, Zaneta
Baxa, Monika
Smatlikova, Petra
Bohuslavova, Bozena
Klempir, Jiri
Nguyen, The Duong
Kuśnierczyk, Anna
Bjørås, Magnar
Klungland, Arne
Hansikova, Hana
Ellederova, Zdenka
Eide, Lars
author_facet Askeland, Georgina
Rodinova, Marie
Štufková, Hana
Dosoudilova, Zaneta
Baxa, Monika
Smatlikova, Petra
Bohuslavova, Bozena
Klempir, Jiri
Nguyen, The Duong
Kuśnierczyk, Anna
Bjørås, Magnar
Klungland, Arne
Hansikova, Hana
Ellederova, Zdenka
Eide, Lars
author_sort Askeland, Georgina
collection PubMed
description Huntington's disease (HD) is a monogenic, progressive, neurodegenerative disorder with currently no available treatment. The Libechov transgenic minipig model for HD (TgHD) displays neuroanatomical similarities to humans and exhibits slow disease progression, and is therefore more powerful than available mouse models for the development of therapy. The phenotypic characterization of this model is still ongoing, and it is essential to validate biomarkers to monitor disease progression and intervention. In this study, the behavioral phenotype (cognitive, motor and behavior) of the TgHD model was assessed, along with biomarkers for mitochondrial capacity, oxidative stress, DNA integrity and DNA repair at different ages (24, 36 and 48 months), and compared with age-matched controls. The TgHD minipigs showed progressive accumulation of the mutant huntingtin (mHTT) fragment in brain tissue and exhibited locomotor functional decline at 48 months. Interestingly, this neuropathology progressed without any significant age-dependent changes in any of the other biomarkers assessed. Rather, we observed genotype-specific effects on mitochondrial DNA (mtDNA) damage, mtDNA copy number, 8-oxoguanine DNA glycosylase activity and global level of the epigenetic marker 5-methylcytosine that we believe is indicative of a metabolic alteration that manifests in progressive neuropathology. Peripheral blood mononuclear cells (PBMCs) were relatively spared in the TgHD minipig, probably due to the lack of detectable mHTT. Our data demonstrate that neuropathology in the TgHD model has an age of onset of 48 months, and that oxidative damage and electron transport chain impairment represent later states of the disease that are not optimal for assessing interventions. This article has an associated First Person interview with the first author of the paper.
format Online
Article
Text
id pubmed-6215428
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher The Company of Biologists Ltd
record_format MEDLINE/PubMed
spelling pubmed-62154282018-11-05 A transgenic minipig model of Huntington's disease shows early signs of behavioral and molecular pathologies Askeland, Georgina Rodinova, Marie Štufková, Hana Dosoudilova, Zaneta Baxa, Monika Smatlikova, Petra Bohuslavova, Bozena Klempir, Jiri Nguyen, The Duong Kuśnierczyk, Anna Bjørås, Magnar Klungland, Arne Hansikova, Hana Ellederova, Zdenka Eide, Lars Dis Model Mech Research Article Huntington's disease (HD) is a monogenic, progressive, neurodegenerative disorder with currently no available treatment. The Libechov transgenic minipig model for HD (TgHD) displays neuroanatomical similarities to humans and exhibits slow disease progression, and is therefore more powerful than available mouse models for the development of therapy. The phenotypic characterization of this model is still ongoing, and it is essential to validate biomarkers to monitor disease progression and intervention. In this study, the behavioral phenotype (cognitive, motor and behavior) of the TgHD model was assessed, along with biomarkers for mitochondrial capacity, oxidative stress, DNA integrity and DNA repair at different ages (24, 36 and 48 months), and compared with age-matched controls. The TgHD minipigs showed progressive accumulation of the mutant huntingtin (mHTT) fragment in brain tissue and exhibited locomotor functional decline at 48 months. Interestingly, this neuropathology progressed without any significant age-dependent changes in any of the other biomarkers assessed. Rather, we observed genotype-specific effects on mitochondrial DNA (mtDNA) damage, mtDNA copy number, 8-oxoguanine DNA glycosylase activity and global level of the epigenetic marker 5-methylcytosine that we believe is indicative of a metabolic alteration that manifests in progressive neuropathology. Peripheral blood mononuclear cells (PBMCs) were relatively spared in the TgHD minipig, probably due to the lack of detectable mHTT. Our data demonstrate that neuropathology in the TgHD model has an age of onset of 48 months, and that oxidative damage and electron transport chain impairment represent later states of the disease that are not optimal for assessing interventions. This article has an associated First Person interview with the first author of the paper. The Company of Biologists Ltd 2018-10-01 2018-10-24 /pmc/articles/PMC6215428/ /pubmed/30254085 http://dx.doi.org/10.1242/dmm.035949 Text en © 2018. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Askeland, Georgina
Rodinova, Marie
Štufková, Hana
Dosoudilova, Zaneta
Baxa, Monika
Smatlikova, Petra
Bohuslavova, Bozena
Klempir, Jiri
Nguyen, The Duong
Kuśnierczyk, Anna
Bjørås, Magnar
Klungland, Arne
Hansikova, Hana
Ellederova, Zdenka
Eide, Lars
A transgenic minipig model of Huntington's disease shows early signs of behavioral and molecular pathologies
title A transgenic minipig model of Huntington's disease shows early signs of behavioral and molecular pathologies
title_full A transgenic minipig model of Huntington's disease shows early signs of behavioral and molecular pathologies
title_fullStr A transgenic minipig model of Huntington's disease shows early signs of behavioral and molecular pathologies
title_full_unstemmed A transgenic minipig model of Huntington's disease shows early signs of behavioral and molecular pathologies
title_short A transgenic minipig model of Huntington's disease shows early signs of behavioral and molecular pathologies
title_sort transgenic minipig model of huntington's disease shows early signs of behavioral and molecular pathologies
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215428/
https://www.ncbi.nlm.nih.gov/pubmed/30254085
http://dx.doi.org/10.1242/dmm.035949
work_keys_str_mv AT askelandgeorgina atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT rodinovamarie atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT stufkovahana atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT dosoudilovazaneta atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT baxamonika atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT smatlikovapetra atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT bohuslavovabozena atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT klempirjiri atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT nguyentheduong atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT kusnierczykanna atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT bjørasmagnar atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT klunglandarne atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT hansikovahana atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT ellederovazdenka atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT eidelars atransgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT askelandgeorgina transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT rodinovamarie transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT stufkovahana transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT dosoudilovazaneta transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT baxamonika transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT smatlikovapetra transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT bohuslavovabozena transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT klempirjiri transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT nguyentheduong transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT kusnierczykanna transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT bjørasmagnar transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT klunglandarne transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT hansikovahana transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT ellederovazdenka transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies
AT eidelars transgenicminipigmodelofhuntingtonsdiseaseshowsearlysignsofbehavioralandmolecularpathologies