Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington\u2019s disease patients

Georgina Askeland,Marie Rodinova,Magnar Bjørås,Arne Klungland,Irena Liskova,Hana Hansikova,Jiri Klempir,Anna Kuśnierczyk,Zaneta Dosoudilova,Lars Eide,Gaute Nesse

doi:10.1038/s41598-018-27985-y

Abstract

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.

Highlights

Huntington’s disease is an autosomal dominant progressive neurodegenerative disorder caused by an inherited, pathogenic expansion of CAG repeats in exon 1 of the huntingtin gene (HTT)
There is partial correlation between onset of disease and total functional capacity (TFC) when age is corrected for (R = 0.61, P < 0.05).To investigate the influence of Huntington’s disease (HD) on mitochondrial function, we assessed the expression of mtDNAand nDNA encoded genes related to mitochondrial pathways
We found significant downregulation of genes related to mitochondrial function in HD peripheral blood mononuclear cells (PBMCs)

Summary

Introduction

Huntington’s disease is an autosomal dominant progressive neurodegenerative disorder caused by an inherited, pathogenic expansion of CAG repeats in exon 1 of the huntingtin gene (HTT). The Unified Huntington’s Disease Rating Score (UHDRS) was established as a reliable hybrid scale to describe motor function, cognitive function, behaviour abnormalities, and total functional capacity (TFC)[5], that together with molecular genetic testing (CAG sizing)[6] provided tools to monitor disease. The mHTT protein in this model influences nuclear gene expression including PGC-1α, the major regulator of mitochondrial biogenesis and result in reduced thermoregulation and reduced expression of the dismutases SOD1 and SOD219. Polyglutamines interfere with mitochondria and disturb intracellular trafficking and cause mitochondrial fragmentation[20,21]

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