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Published on: June 23, 2023
Altered Mitochondrial DNA Methylation Pattern in Alzheimer Disease-Related Pathology and in Parkinson Disease
Marta Blanch1, Jose Luis Mosquera2, Belén Ansoleaga1
1Institute of Neuropathology, Bellvitge University Hospital (Bellvitge Biomedical Research Institute) IDIBELL, L'Hospitalet de Llobregat, Spain.
Abstract:
Mitochondrial dysfunction is linked with the etiopathogenesis of Alzheimer disease and Parkinson disease. Mitochondria are intracellular organelles essential for cell viability and are characterized by the presence of the mitochondrial (mt)DNA. DNA methylation is a well-known epigenetic mechanism that regulates nuclear gene transcription. However, mtDNA methylation is not the subject of the same research attention. The present study shows the presence of mitochondrial 5-methylcytosine in CpG and non-CpG sites in the entorhinal cortex and substantia nigra of control human postmortem brains, using the 454 GS FLX Titanium pyrosequencer. Moreover, increased mitochondrial 5-methylcytosine levels are found in the D-loop region of mtDNA in the entorhinal cortex in brain samples with Alzheimer disease-related pathology (stages I to II and stages III to IV of Braak and Braak; n = 8) with respect to control cases. Interestingly, this region shows a dynamic pattern in the content of mitochondrial 5-methylcytosine in amyloid precursor protein/presenilin 1 mice along with Alzheimer disease pathology progression (3, 6, and 12 months of age). Finally, a loss of mitochondrial 5-methylcytosine levels in the D-loop region is found in the substantia nigra in Parkinson disease (n = 10) with respect to control cases. In summary, the present findings suggest mtDNA epigenetic modulation in human brain is vulnerable to neurodegenerative disease states.
Insights
Epigenetic changes in mitochondrial DNA (mtDNA) methylation are linked to neurodegenerative diseases. This study found altered mtDNA methylation in Alzheimer
Area of Science:
- Neuroscience
- Epigenetics
- Mitochondrial Biology
Background:
- Mitochondrial dysfunction is implicated in Alzheimer's and Parkinson's diseases.
- Mitochondrial DNA (mtDNA) methylation is an understudied epigenetic mechanism.
- Epigenetic regulation is crucial for nuclear gene transcription.
Purpose of the Study:
- To investigate the presence and role of mtDNA methylation in human brain regions relevant to neurodegenerative diseases.
- To analyze changes in mtDNA methylation patterns in Alzheimer's and Parkinson's disease.
Main Methods:
- Utilized 454 GS FLX Titanium pyrosequencing to detect 5-methylcytosine in mtDNA from human postmortem brains (entorhinal cortex and substantia nigra).
- Examined mtDNA methylation in Alzheimer's disease (Braak stages I-IV) and Parkinson's disease cases compared to controls.
- Analyzed dynamic changes in mtDNA methylation in a mouse model of Alzheimer's disease.
Main Results:
- Confirmed the presence of 5-methylcytosine at CpG and non-CpG sites in mtDNA from control human brains.
- Observed increased mtDNA methylation in the D-loop region in the entorhinal cortex of Alzheimer's disease patients.
- Detected dynamic changes in mtDNA methylation during Alzheimer's disease progression in mice.
- Found decreased mtDNA methylation in the D-loop region in the substantia nigra of Parkinson's disease patients.
Conclusions:
- Mitochondrial DNA methylation is present in key human brain regions.
- mtDNA methylation patterns are altered in Alzheimer's and Parkinson's diseases.
- These findings suggest mtDNA epigenetic modulation is vulnerable in neurodegeneration.
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