Cargando…
Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington’s disease patients
Huntington’s disease (HD) is a progressive neurodegenerative disorder primarily affecting the basal ganglia and is caused by expanded CAG repeats in the huntingtin gene. Except for CAG sizing, mitochondrial and nuclear DNA (mtDNA and nDNA) parameters have not yet proven to be representative biomarke...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026140/ https://www.ncbi.nlm.nih.gov/pubmed/29959348 http://dx.doi.org/10.1038/s41598-018-27985-y |
_version_ | 1783336392703606784 |
---|---|
author | Askeland, Georgina Dosoudilova, Zaneta Rodinova, Marie Klempir, Jiri Liskova, Irena Kuśnierczyk, Anna Bjørås, Magnar Nesse, Gaute Klungland, Arne Hansikova, Hana Eide, Lars |
author_facet | Askeland, Georgina Dosoudilova, Zaneta Rodinova, Marie Klempir, Jiri Liskova, Irena Kuśnierczyk, Anna Bjørås, Magnar Nesse, Gaute Klungland, Arne Hansikova, Hana Eide, Lars |
author_sort | Askeland, Georgina |
collection | PubMed |
description | Huntington’s disease (HD) is a progressive neurodegenerative disorder primarily affecting the basal ganglia and is caused by expanded CAG repeats in the huntingtin gene. Except for CAG sizing, mitochondrial and nuclear DNA (mtDNA and nDNA) parameters have not yet proven to be representative biomarkers for disease and future therapy. Here, we identified a general suppression of genes associated with aerobic metabolism in peripheral blood mononuclear cells (PBMCs) from HD patients compared to controls. In HD, the complex II subunit SDHB was lowered although not sufficiently to affect complex II activity. Nevertheless, we found decreased level of factors associated with mitochondrial biogenesis and an associated dampening of the mitochondrial DNA damage frequency in HD, implying an early defect in mitochondrial activity. In contrast to mtDNA, nDNA from HD patients was four-fold more modified than controls and demonstrated that nDNA integrity is severely reduced in HD. Interestingly, the level of nDNA damage correlated inversely with the total functional capacity (TFC) score; an established functional score of HD. Our data show that PBMCs are a promising source to monitor HD progression and highlights nDNA damage and diverging mitochondrial and nuclear genome responses representing early cellular impairments in HD. |
format | Online Article Text |
id | pubmed-6026140 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-60261402018-07-09 Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington’s disease patients Askeland, Georgina Dosoudilova, Zaneta Rodinova, Marie Klempir, Jiri Liskova, Irena Kuśnierczyk, Anna Bjørås, Magnar Nesse, Gaute Klungland, Arne Hansikova, Hana Eide, Lars Sci Rep Article Huntington’s disease (HD) is a progressive neurodegenerative disorder primarily affecting the basal ganglia and is caused by expanded CAG repeats in the huntingtin gene. Except for CAG sizing, mitochondrial and nuclear DNA (mtDNA and nDNA) parameters have not yet proven to be representative biomarkers for disease and future therapy. Here, we identified a general suppression of genes associated with aerobic metabolism in peripheral blood mononuclear cells (PBMCs) from HD patients compared to controls. In HD, the complex II subunit SDHB was lowered although not sufficiently to affect complex II activity. Nevertheless, we found decreased level of factors associated with mitochondrial biogenesis and an associated dampening of the mitochondrial DNA damage frequency in HD, implying an early defect in mitochondrial activity. In contrast to mtDNA, nDNA from HD patients was four-fold more modified than controls and demonstrated that nDNA integrity is severely reduced in HD. Interestingly, the level of nDNA damage correlated inversely with the total functional capacity (TFC) score; an established functional score of HD. Our data show that PBMCs are a promising source to monitor HD progression and highlights nDNA damage and diverging mitochondrial and nuclear genome responses representing early cellular impairments in HD. Nature Publishing Group UK 2018-06-29 /pmc/articles/PMC6026140/ /pubmed/29959348 http://dx.doi.org/10.1038/s41598-018-27985-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Askeland, Georgina Dosoudilova, Zaneta Rodinova, Marie Klempir, Jiri Liskova, Irena Kuśnierczyk, Anna Bjørås, Magnar Nesse, Gaute Klungland, Arne Hansikova, Hana Eide, Lars Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington’s disease patients |
title | Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington’s disease patients |
title_full | Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington’s disease patients |
title_fullStr | Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington’s disease patients |
title_full_unstemmed | Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington’s disease patients |
title_short | Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington’s disease patients |
title_sort | increased nuclear dna damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from huntington’s disease patients |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026140/ https://www.ncbi.nlm.nih.gov/pubmed/29959348 http://dx.doi.org/10.1038/s41598-018-27985-y |
work_keys_str_mv | AT askelandgeorgina increasednucleardnadamageprecedesmitochondrialdysfunctioninperipheralbloodmononuclearcellsfromhuntingtonsdiseasepatients AT dosoudilovazaneta increasednucleardnadamageprecedesmitochondrialdysfunctioninperipheralbloodmononuclearcellsfromhuntingtonsdiseasepatients AT rodinovamarie increasednucleardnadamageprecedesmitochondrialdysfunctioninperipheralbloodmononuclearcellsfromhuntingtonsdiseasepatients AT klempirjiri increasednucleardnadamageprecedesmitochondrialdysfunctioninperipheralbloodmononuclearcellsfromhuntingtonsdiseasepatients AT liskovairena increasednucleardnadamageprecedesmitochondrialdysfunctioninperipheralbloodmononuclearcellsfromhuntingtonsdiseasepatients AT kusnierczykanna increasednucleardnadamageprecedesmitochondrialdysfunctioninperipheralbloodmononuclearcellsfromhuntingtonsdiseasepatients AT bjørasmagnar increasednucleardnadamageprecedesmitochondrialdysfunctioninperipheralbloodmononuclearcellsfromhuntingtonsdiseasepatients AT nessegaute increasednucleardnadamageprecedesmitochondrialdysfunctioninperipheralbloodmononuclearcellsfromhuntingtonsdiseasepatients AT klunglandarne increasednucleardnadamageprecedesmitochondrialdysfunctioninperipheralbloodmononuclearcellsfromhuntingtonsdiseasepatients AT hansikovahana increasednucleardnadamageprecedesmitochondrialdysfunctioninperipheralbloodmononuclearcellsfromhuntingtonsdiseasepatients AT eidelars increasednucleardnadamageprecedesmitochondrialdysfunctioninperipheralbloodmononuclearcellsfromhuntingtonsdiseasepatients |