Scientists Learn How Abnormal DNA Repetitions in a Gene Cause Neuron Death In ALS

Scientists have known for some time that abnormal DNA repetitions in the C9orf72 gene contribute to neuron death in ALS and frontotemporal dementia.

Now they have learned how it happens: The anomalies leave DNA susceptible to damage, prompting a cell repair mechanism to become over-active. That hyperactivity cause neuron deaths.

The study, “C9orf72 expansion disrupts ATM-mediated chromosomal break repair,” was published in the Nature Neuroscience.

Too many DNA repetitions in the C9orf72 gene are “the most common genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia,” the researchers wrote. “Growing evidence suggests that C9orf72 repeat expansions also contribute to a wide spectrum of neurodegenerative diseases, such as Alzheimer’s, Huntington’s, multiple sclerosis, Parkinson’s disease and cerebellar ataxias.”

The team wanted to learn how the DNA expansions in the C9orf72 gene trigger neuron death in ALS and frontotemporal dementia. Studying neurons in human tissue and rats, they discovered that the expansions interact with RNA molecules to form what are called R-loops.

R-loops make DNA more susceptible to breaking. This susceptibility triggers the excessive activation of a cell repair mechanism called autophagy.

Autophagy is useful to cells that need to eliminate and recycle old or faulty molecules or components. But if it is too active, cells end up eating themselves, leading to neuron death.

The researchers were able to prevent neuron damage by fine-tuning the activity of DNA repair mechanisms.

“We were able to shut down the out-of-control degradation process, which runs down the cell’s ability to fix genomic breaks,” Sherif El-Khamisy, the study’s co-senior author, said in a news release written by Clara Rodríguez Fernández. “Even though the DNA was still damaged, the cells were able to cope and did not die.”

By learning how DNA repetitions cause neuron death, the team believes it has helped the scientific community take a step toward understanding the mechanisms underlying the development of movement  neuron diseases such as ALS.

“More research needs to be done, but it’s possible that this newly discovered mechanism contributes to the death of nerve cells in people suffering from diseases such as Alzheimer’s, Parkinson’s and during the aging process,” El-Khamisy said. “I’m really excited [that], if we modulate this degradation process, we can preserve our DNA repair toolkit and take away the pathology, the cell death.”