Mitochondrial DNA Copy Number and D-Loop Region Methylation in Carriers of Amyotrophic Lateral Sclerosis Gene Mutations

Abstract

Aim: To investigate mitochondrial DNA (mtDNA) copy number and D-loop region methylation in carriers of SOD1, TARDBP, FUS and C9orf72 mutations. Methods: Investigations were performed in blood DNA from 114 individuals, including amyotrophic lateral sclerosis (ALS) patients, presymptomatic carriers and noncarrier family members. Results: Increased mtDNA copy number (p = 0.0001) was observed in ALS patients, and particularly in those with SOD1 or C9orf72 mutations. SOD1 mutation carriers showed also a significant decrease in D-loop methylation levels (p = 0.003). An inverse correlation between D-loop methylation levels and the mtDNA copy number (p = 0.0005) was observed. Conclusion: Demethylation of the D-loop region could represent a compensatory mechanism for mtDNA upregulation in carriers of ALS-linked SOD1 mutations.

Keywords::

• amyotrophic lateral sclerosis
• D-loop mitochondrial region
• epigenetics
• mitochondrial DNA methylation
• mtDNA copy number
• SOD1

Supplementary data

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Acknowledgements

This manuscript is dedicated to the memory of S Penco who passed away on 13 April 2017. She largely inspired the research carried out in this manuscript.

Financial & competing interest disclosure

This work was supported by researcher’s intramural funds (ATENEO Funds, University of Pisa) and by a grant from ‘ASSOCIAZIONE IO CORRO CON GIOVANNI’, www.iocorrocongiovanni.org; [email protected]; Paina di Giussano – Via IV Novembre 20 – c/o Centro Associativo ‘Generazioni’. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by researcher’s intramural funds (ATENEO Funds, University of Pisa) and by a grant from ‘ASSOCIAZIONE IO CORRO CON GIOVANNI’, www.iocorrocongiovanni.org; [email protected]; Paina di Giussano – Via IV Novembre 20 – c/o Centro Associativo ‘Generazioni’. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.