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Reduced mtDNA Copy Number in the Prefrontal Cortex of C9ORF72 Patients

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Abstract

Hexanucleotide repeat expansion in C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Loss of C9ORF72 protein function and a toxic gain-of-function directly by the RNA or RAN translation have been proposed as triggering pathological mechanisms, along with the accumulation of TDP-43 protein. In addition, mitochondrial defects have been described to be a major driver of disease initiation. Mitochondrial DNA copy number has been proposed as a useful biomarker of mitochondrial dysfunction. The aim of our study was to determine the presence of mtDNA copy number alterations in C9ALS/FTD patients. Therefore, we assessed mtDNA copy number in postmortem prefrontal cortex from 18 C9ORF72 brain donors and 9 controls using digital droplet PCR. A statistically significant decrease of 50% was obtained when comparing C9ORF72 samples and controls. This decrease was independent of age and sex. The reduction of mtDNA copy number was found to be higher in patients’ samples presenting abundant TDP-43 protein inclusions. A growing number of studies demonstrated the influence of mtDNA copy number reduction on neurodegeneration. Our results provide new insights into the role of mitochondrial dysfunction in the pathogenesis of C9ALS/FTD.

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Availability of Data and Material

The datasets of the current study are available upon request with no restriction.

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Acknowledgements

We are grateful to the Neurological Tissue Bank of the Biobanc Hospital Clinic-IDIBAPS, Barcelona, Spain, for the sample and data procurement. We thank patients and relatives for generous brain donation for research. We thank Núria Serra for providing technical assistance in ddPCR experiments. The CIBER de Enfermedades Raras y Neurodegenerativas are initiatives of the Instituto de Salud Carlos III. Preliminary data was presented in the 53rd European Society of Human Genetics (ESHG) Conference as an interactive e-Poster, June 6-9, 2020 (Eur J Hum Genet 28, 141–797 (2020). https://doi.org/10.1038/s41431-020-00739-z).

Funding

This work was supported by the Instituto de Salud Carlos III (PI17/01067), co-financed by Fondo Europeo de Desarrollo Regional (FEDER) “una manera de hacer Europa,” AGAUR from the Autonomous Catalan Government (2017SGR1134), and Ministerio de Ciencia, Innovación y Universidades (SAF2017-89791-R).

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Authors and Affiliations

  1. Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona, C/Villarroel, 170, 08036, Barcelona, Spain

    Maria Isabel Alvarez-Mora, Teresa Riazuelo & Laia Rodriguez-Revenga

  2. CIBER of Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain

    Maria Isabel Alvarez-Mora & Laia Rodriguez-Revenga

  3. Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain

    Maria Isabel Alvarez-Mora & Laia Rodriguez-Revenga

  4. CIBER of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain

    Petar Podlesniy

  5. Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS, Barcelona, Spain

    Laura Molina-Porcel

  6. Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain

    Laura Molina-Porcel

  7. Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria

    Ellen Gelpi

Authors
  1. Maria Isabel Alvarez-Mora
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  2. Petar Podlesniy
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  3. Teresa Riazuelo
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  4. Laura Molina-Porcel
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  5. Ellen Gelpi
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  6. Laia Rodriguez-Revenga
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Contributions

Maria Isabel Alvarez-Mora: formulation and evolution of overarching research goals. Preparation and presentation of the published work

Petar Podlesniy: development and design of methodology

Teresa Riazuelo and Nuria Serra: conducting research and investigation process

Laura Molina: provision of study materials and preparation of the published work

Ellen Gelpi: preparation and presentation of the published work and critical review.

Laia Rodriguez-Revenga: formulation and evolution of overarching research goals. Preparation and presentation of the published work

Corresponding author

Correspondence to Laia Rodriguez-Revenga.

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Ethics Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of the Hospital Clinic of Barcelona. Brain samples were obtained from the Hospital Clinic-IDIBAPS Brain Bank under approved protocols of the Ethical Committee (Hospital Clinic Barcelona, Spain).

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Alvarez-Mora, M.I., Podlesniy, P., Riazuelo, T. et al. Reduced mtDNA Copy Number in the Prefrontal Cortex of C9ORF72 Patients. Mol Neurobiol 59, 1230–1237 (2022). https://doi.org/10.1007/s12035-021-02673-7

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  • DOI: https://doi.org/10.1007/s12035-021-02673-7

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