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Updated: Apr 27, 2026
Genotyping Single Nucleotide Polymorphisms in the Mitochondrial Genome by Pyrosequencing
Published on: February 10, 2023
Differential mtDNA damage patterns in a transgenic mouse model of Machado-Joseph disease (MJD/SCA3)
Amanda Ramos1, Nadiya Kazachkova, Francisca Silva
1Centre of Research in Natural Resources (CIRN), Department of Biology, University of the Azores, Ponta Delgada, Portugal, amanda.ramos.reche@gmail.com.
Abstract:
Mitochondrial dysfunction has been associated with late onset neurodegenerative disorders, among which is Machado-Joseph disease (MJD/SCA3). In a previous study, using a transgenic mouse model of MJD, we reported a decrease in mitochondrial DNA (mtDNA) copy number and an accumulation of the 3876-bp deletion with age and with phenotype development. We extended this study by analyzing the pattern of mtDNA depletion and the accumulation of the 3876-bp deletion in 12 older transgenic (TG) and 4 wild-type (wt) animals, and by investigating the accumulation of somatic mutations in the D-loop region in 76 mice (42 TG and 34 wt). mtDNA damage was studied in TG and wt mice at different ages and tissues (blood, pontine nuclei, and hippocampus). Results for older mice demonstrate an accumulation of the mtDNA 3867-bp deletion with age, which was more pronounced in TG animals. Furthermore, the tendency for mtDNA copy number decrease with age, in all analyzed tissues of TG and wt animals, was also confirmed. No point mutations were detected in the D-loop, neither in TG nor wt animals, in any of the tissues analyzed. Due to the absence of mtDNA somatic mutations, we can suggest that mtDNA point mutation accumulation cannot be used to monitor the development and progression of the phenotype in this mouse model and likely in any MJD mice model. The present results further confirm not only the association between mtDNA alterations (copy number and deletions) and age, but also between such alterations and the expression of the mutant ataxin-3 in TG mice.
Insights
Mitochondrial DNA (mtDNA) deletions and copy number decrease with age in Machado-Joseph disease (MJD/SCA3) mouse models. These mtDNA alterations correlate with mutant ataxin-3 expression, but point mutations do not track disease progression.
Area of Science:
- Neuroscience
- Genetics
- Mitochondrial Biology
Background:
- Mitochondrial dysfunction is linked to late-onset neurodegenerative disorders like Machado-Joseph disease (MJD/SCA3).
- Previous studies in MJD mouse models showed decreased mitochondrial DNA (mtDNA) copy number and increased mtDNA deletions with age and disease progression.
Purpose of the Study:
- To further investigate mtDNA depletion and the accumulation of a specific mtDNA deletion (3876-bp) in older MJD transgenic (TG) mice compared to wild-type (wt) controls.
- To examine the accumulation of somatic mutations in the D-loop region of mtDNA in MJD mice.
- To analyze mtDNA damage across different ages and tissues (blood, pontine nuclei, hippocampus).
Main Methods:
- Analysis of mtDNA copy number and the 3876-bp deletion in 12 older TG and 4 wt mice.
- Investigation of somatic mutations in the D-loop region of mtDNA in 76 mice (42 TG, 34 wt).
- Comparative analysis of mtDNA damage in TG and wt mice at various ages and in different tissues.
Main Results:
- An age-dependent accumulation of the mtDNA 3867-bp deletion was observed, being more pronounced in TG mice.
- A decrease in mtDNA copy number with age was confirmed across all analyzed tissues in both TG and wt animals.
- No point mutations were detected in the D-loop region of mtDNA in either TG or wt mice, regardless of tissue or age.
Conclusions:
- mtDNA alterations, specifically deletions and reduced copy number, are associated with aging and the expression of mutant ataxin-3 in MJD mice.
- The absence of detectable mtDNA point mutations suggests they are not suitable biomarkers for monitoring MJD progression in this model.
- These findings reinforce the link between mitochondrial health and the pathogenesis of Machado-Joseph disease.
