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Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from

Georgina Askeland1,2, Zaneta Dosoudilova3, Marie Rodinova3

  • 1Department of Medical Biochemistry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Scientific Reports
|July 1, 2018
PubMed

Insights

Huntington's disease (HD) involves impaired aerobic metabolism and reduced mitochondrial activity. Nuclear DNA damage significantly increases in HD patients, correlating with disease severity and offering a potential biomarker.

Area of Science:

  • Genetics
  • Neuroscience
  • Cell Biology

Background:

  • Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the huntingtin gene.
  • Current biomarkers for HD are limited, necessitating the identification of new markers for disease progression and therapeutic monitoring.

Purpose of the Study:

  • To investigate mitochondrial and nuclear DNA (mtDNA and nDNA) parameters as potential biomarkers in peripheral blood mononuclear cells (PBMCs) of HD patients.
  • To explore cellular impairments, including metabolic and genomic integrity, associated with Huntington's disease.

Main Methods:

  • Analysis of gene expression related to aerobic metabolism in PBMCs from HD patients and controls.
  • Quantification of mtDNA damage frequency and assessment of nDNA modification levels.
  • Correlation of genomic damage with the Total Functional Capacity (TFC) score in HD patients.

Main Results:

  • A general suppression of aerobic metabolism genes was observed in HD patient PBMCs.
  • Decreased levels of factors for mitochondrial biogenesis and reduced mtDNA damage frequency suggest early mitochondrial dysfunction.
  • HD patients exhibited a four-fold increase in nDNA modification compared to controls, with nDNA damage inversely correlating with TFC score.

Conclusions:

  • PBMCs represent a viable source for monitoring Huntington's disease progression.
  • Increased nDNA damage and distinct mitochondrial and nuclear genome responses indicate early cellular impairments in HD.
  • These findings highlight nDNA damage as a potential biomarker for HD severity and progression.

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