Mitochondrial genetics shed light on ALS Risk and protection

Using sequencing techniques, researchers associated 51 mutations in mitochondrial DNA with amyotrophic lateral sclerosis (ALS), an incurable degenerative neurological disorder that leads to muscle atrophy and paralysis. Thirteen of the mutations increased the risk of ALS, while 38 were protective. The study suggests these mutations may be important for future tests and research on ALS.

It is worth recalling that mitochondria, the organelles that produce energy for cells, have their own DNA (mtDNA), which is inherited solely from the mother. Mutations in mtDNA can cause several diseases, almost all of which affect neuromuscular processes.

Briones, who is co-corresponding author alongside James Broach, a researcher at Penn State College of Medicine in the U.S., stressed the importance of their findings.

Multidisciplinary

The group analyzed mtDNA, which is unique because it is inherited solely from the mother, whereas nuclear DNA is inherited from both parents. Hereditary genetic factors are the main cause of ALS cases – only 10% are due to a genetic defect. In practice, the patient's neurons degrade or die, ceasing to "send messages" to the muscles.

The SNVs associated with increased risk of ALS had odds ratios higher than 1; the protective SNVs had odds ratios lower than 1. Odds ratio is a statistical parameter used in epidemiology to estimate the odds (probability) of an event for an exposed group.

P-value (probability value) is the probability of obtaining the sampling results due to chance. The smaller the p-value, the stronger the evidence that the results are significant and not due to chance. In biology, a p-value of less than 0.05 is considered significant.

Mendelian inheritance is not always observed in ALS, where extranuclear or cytoplasmic inheritance, especially via mutations in mtDNA, is frequent. This is another reason for the relevance of the study.

The Brazilian researchers now want to analyze the available data using artificial intelligence. They also plan to sequence samples from a cohort of Brazilian patients and plot the results against the 51 mutations detected in the study.

Source:

São Paulo Research Foundation

Journal reference:

Briones, M. R. S., et al. (2024). Mitochondrial genome variants associated with amyotrophic lateral sclerosis and their haplogroup distribution. Muscle & Nerve. doi.org/10.1002/mus.28230.