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Reduced mtDNA Copy Number in the Prefrontal Cortex of C9ORF72 Patients
Maria Isabel Alvarez-Mora1,2,3, Petar Podlesniy4, Teresa Riazuelo1
1Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona, C/Villarroel, 170, 08036, Barcelona, Spain.
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.
Insights
Mitochondrial DNA copy number is significantly reduced in C9ALS/FTD patients, suggesting mitochondrial dysfunction contributes to neurodegeneration in this common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Hexanucleotide repeat expansion in the C9ORF72 gene is the leading genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD).
- Pathological mechanisms involve C9ORF72 protein loss, RNA toxicity, RAN translation, TDP-43 accumulation, and mitochondrial dysfunction.
- Mitochondrial DNA (mtDNA) copy number serves as a biomarker for mitochondrial dysfunction.
Purpose of the Study:
- To investigate alterations in mtDNA copy number in C9ALS/FTD patients.
- To explore the relationship between mtDNA copy number and disease pathology.
Main Methods:
- Assessed mtDNA copy number in postmortem prefrontal cortex samples from 18 C9ALS/FTD patients and 9 controls.
- Utilized digital droplet PCR for precise quantification of mtDNA copy number.
Main Results:
- A significant 50% decrease in mtDNA copy number was observed in C9ALS/FTD patients compared to controls.
- This reduction was independent of patient age and sex.
- Lower mtDNA copy number correlated with higher levels of TDP-43 protein inclusions.
Conclusions:
- Mitochondrial dysfunction, indicated by reduced mtDNA copy number, plays a role in C9ALS/FTD pathogenesis.
- These findings highlight the importance of mitochondrial defects in neurodegeneration associated with C9ORF72 expansions.
