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Accumulation of Mitochondrial DNA Common Deletion Since The Preataxic Stage of Machado-Joseph Disease

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Abstract

Molecular alterations reflecting pathophysiologic changes thought to occur many years before the clinical onset of Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3), a late-onset polyglutamine disorder, remain unidentified. The absence of molecular biomarkers hampers clinical trials, which lack sensitive measures of disease progression, preventing the identification of events occurring prior to clinical onset. Our aim was to analyse the mtDNA content and the amount of the common deletion (m.8482_13460del4977) in a cohort of 16 preataxic MJD mutation carriers, 85 MJD patients and 101 apparently healthy age-matched controls. Relative expression levels of RPPH1, MT-ND1 and MT-ND4 genes were assessed by quantitative real-time PCR. The mtDNA content was calculated as the difference between the expression levels of a mitochondrial gene (MT-ND1) and a nuclear gene (RPPH1); the amount of mtDNA common deletion was calculated as the difference between expression levels of a deleted (MT-ND4) and an undeleted (MT-ND1) mitochondrial genes. mtDNA content in MJD carriers was similar to that of healthy age-matched controls, whereas the percentage of the common deletion was significantly increased in MJD subjects, and more pronounced in the preclinical stage (p < 0.05). The BCL2/BAX ratio was decreased in preataxic carriers compared to controls, suggesting that the mitochondrial-mediated apoptotic pathway is altered in MJD. Our findings demonstrate for the first time that accumulation of common deletion starts in the preclinical stage. Such early alterations provide support to the current understanding that any therapeutic intervention in MJD should start before the overt clinical phenotype.

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Funding

This work was funded by FEDER funds through the Operational Competitiveness Programme—COMPETE and by National Funds through FCT—Fundação para a Ciência e a Tecnologia under the project FCOMP-01-0124-FEDER-028753 (PTDC/DTP/PIC/0370/2012). A PhD fellowship M3.1.2/F/006/2011 (MR) and postdoctoral fellowships M3.1.7/F/031/2011 (AR) and M3.1.3/F/004/2009 (NK) were supported by Fundo Regional para a Ciência (FRC), Governo dos Açores. CB is supported by the Wellcome Trust (UK).

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Authors and Affiliations

  1. Faculdade de Ciências e Tecnologia, Universidade dos Açores (UAc), Ponta Delgada, Portugal

    Mafalda Raposo, Amanda Ramos, Nadiya Kazachkova, Balbina Teixeira & Manuela Lima

  2. Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Porto, Portugal

    Mafalda Raposo, Amanda Ramos, Nadiya Kazachkova & Manuela Lima

  3. Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal

    Mafalda Raposo, Amanda Ramos, Nadiya Kazachkova & Manuela Lima

  4. Unitat d’Antropologia Biològica, Dep. Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autònoma de Barcelona, Cerdanyola del Valles, Spain

    Amanda Ramos & Cristina Santos

  5. Department of Clinical and Experimental Epilepsy and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK

    Conceição Bettencourt

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  1. Mafalda Raposo
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  2. Amanda Ramos
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  3. Cristina Santos
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  4. Nadiya Kazachkova
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Correspondence to Mafalda Raposo.

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Raposo, M., Ramos, A., Santos, C. et al. Accumulation of Mitochondrial DNA Common Deletion Since The Preataxic Stage of Machado-Joseph Disease. Mol Neurobiol 56, 119–124 (2019). https://doi.org/10.1007/s12035-018-1069-x

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