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Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington's disease patients

G. Askeland, Z. Dosoudilova, M. Rodinova, J. Klempir, I. Liskova, A. Kuśnierczyk, M. Bjørås, G. Nesse, A. Klungland, H. Hansikova, L. Eide,

. 2018 ; 8 (1) : 9817. [pub] 20180629

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc19045390

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.

Citace poskytuje Crossref.org

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$a Dosoudilova, Zaneta $u Department of Pediatrics and Adolescent Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
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$a Klempir, Jiri $u Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
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$a Liskova, Irena $u Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
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$a Bjørås, Magnar $u Department of Microbiology, Oslo University Hospital, Oslo, Norway. Proteomics and Metabolomics Core Facility, PROMEC, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
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$a Nesse, Gaute $u Department of Microbiology, Oslo University Hospital, Oslo, Norway.
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$a Klungland, Arne $u Department of Microbiology, Oslo University Hospital, Oslo, Norway.
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$a Hansikova, Hana $u Department of Pediatrics and Adolescent Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
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$a Eide, Lars $u Department of Medical Biochemistry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. lars.eide@medisin.uio.no.
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