While changes in the genetic code usually get attention because they cause disease, there are some genetic mutations that can have a beneficial or protective effect. Reporting in Nature Neuroscience, scientists have now found some of those mutations, and research has indicated that they help shield people from a neurodegenerative disorder known as amyotrophic lateral sclerosis (ALS). Though it's adjacent to a protein coding region, these genetic mutations are in a region of DNA that does not code for protein. Non-coding regions make up around 97 percent of our genome, and scientists are still learning more about their functions. Once considered 'junk' DNA, the importance of non-coding regions are increasingly being recognized; many have been linked to regulation of the genome, for example.
"This massive, noncoding part of the genome has been overlooked in the search for the genetic origins of neurodegenerative diseases like ALS. This is despite the fact that for most ALS cases, proteins cannot explain the emergence of the disease," noted senior study author Professor Eran Hornstein of the Weizmann Institute of Science.
ALS is a rare disorder in which motor neurons, which are responsible for muscle movement, begin to die off. At the start, this causes problems with walking or talking, but as the disease progresses, neurons that control functions such as breathing also die, land the disorder is fatal.
The death of neurons in the brain triggers the immune system to respond. Immune cells there called microglia spring into action, and try to attack the cause of the neurodegeneration, explained study co-author Dr. Chen Eitan.
But there is such severe neurodegeneration in ALS patients, the microglia become chronically activated, leading to toxicity in the brain. Even more motor neurons can be lost as the activity of the immune system spirals out of control.
A gene called IL18RAP is known to influence microglia, and like many genes, there are genetic sequences near that gene that are not translated into protein; it has a so-called untranslated region (UTR). In this study, the scientists focused on the UTR of IL18RAP; they identified mutations there that can mitigate the toxic effects of microglia overactivation. This study showed that mutations in this gene's UTR can reduce inflammation, noted Eitan.
In this research, the investigators analyzed the genomes of over 76,000 people, including more than 6,000 ALS patients. This revealed that mutations in the IL18RAP UTR can reduce the risk of ALS almost five times. The mutations were found in ALS patients only in rare cases. When an ALS patient did carry one of those protective mutations, the onset of their disease tended to be about six years later compared to patients without the mutations. The researchers suggested that the mutations are influencing a basic part of ALS, and can slow neurodegeneration.
The findings were confirmed when the mutations were introduced in stem cells from ALS patients. The cells were cultured in the lab as microglia; those with protective mutations were not as active against motor neurons compared to microglia without the mutations. Motor neurons were able to survive much longer when they were grown with mutated microglia, as seen in the video.
This research could lead to new treatments for ALS patients, and highlighted the importance of non-coding regions, added Eitan.