Scientists at the Weizmann Institute of Science have discovered a new pathway that may protect nerve cells in the brain and slow the development of degenerative brain disease
It is said that the best defense is an attack, but when the battlefield is the human brain – too sharp an attack on the immune system can lead to defeat. This is exactly the case with lateral amyotrophic sclerosis (ALS), a rare disease that attacks the motor nerve cells necessary for voluntary movement of body muscles – from the movement of the legs to the functioning of the respiratory system. Awareness of ALS rose a few years ago thanks to the ice bucket challenge that swept social media, but unfortunately – the disease remains incurable, and the search for treatments – is still in full swing. In a new study whose results are published today in the scientific journal Nature NeuroscienceScientists from the Weizmann Institute of Science reveal that mutations in it may regulate the defense mechanisms of the brain, and thus, perhaps, slow down the development of ALS.
One of the symptoms of ALS – inflammation in the areas of activation of the motor nerve cells in the brain
One of the symptoms of ALS is inflammation that develops in areas of the brain associated with motor neuron activity. “The brain has its own immune system,” explains Dr. Chen Eitan of Prof. Eran Hornstein’s group in the Departments of Molecular Genetics and Molecular Neurobiology, who co-led the study with research student Aviad Siani. ‘- They will try to protect it, and attack the source of the neurodegeneration.’
“In the search for the genetic origin of degenerative brain diseases like ALS, not much importance has so far been attached to a region in the genome that does not encode proteins,” says Prof. Hornstein, whose research in his lab focuses precisely on this unknown territory. “Until recently the role of this region was so vague that it became known as the ‘biological dark matter’, and like the physical dark matter – it also occupies a huge share: more than 97% of our genome does not encode proteins.” It is now known that this part of the genome serves as an “activation guide”, which regulates, among other things, the action of the genes encoding proteins. The current study by Prof. Hornstein and members of his group focused on the IL18RAP gene known to be associated with microglial action. Their findings suggest that an unencoded region in this gene may contain mutations capable of reducing the harmful effect of microglia in ALS. This is a particularly surprising discovery, since the presence of genetic mutations does not often constitute good news in the context of the onset of disease.
To achieve these results, the researchers first analyzed the genomes of more than 6,000 ALS patients and more than 70,000 healthy people. The analysis showed that the chance of developing ALS is almost five times lower in people with mutations in the IL18RAP gene. In fact, it was almost impossible to detect ALS patients with these mutations, and in the rare cases in which such mutations were identified, their disease broke out about six years later, on average, compared to patients without the mutations. Following the findings, the researchers hypothesized that the mutations in the gene affect the core processes associated with the disease, and that their presence slows its development.
In order to confirm their hypothesis about the “defensive mutations”, the scientists used advanced gene editing tools and inserted the mutations into the stem cells of ALS patients. These “arranged” stem cells were “matured” into microglial cells and grown in culture alongside motor neurons. The researchers showed that the microglial cells with the mutations responded more moderately – that is, less violently – to the motor cells, compared to the microglial cells without the mutations. “Nerve cells have survived, significantly longer, when they culturally encountered the microglial cells with the defensive mutations,” Siani says.
[embedded content]
These findings have potential implications for future research in the field of degenerative brain diseases. “In fact, we have discovered a new pathway that may protect brain cells,” says Dr. Eitan. “In future studies we will need to examine whether regulating this pathway can indeed have a positive effect on ALS patients. In a broader context, the findings suggest that the unencoded genome should not be ignored – not only in ALS research, but in any disease with genetic components. “
More on the subject on the Knowledge website: