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Mutations in noncoding DNA are found to protect the brain from ALS

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Genetic mutations associated with the disease often give a bad report. Mutations in more than 25 cells, for example, are associated with amyotrophic lateral sclerosis, or ALS, and all increase the risk of developing this incurable disease. Now, a research team led by Professor Eran Hornstein of the Weizmann Institute of Science, has linked a new gene to ALS, but this contains several mutations: They seem to play a role in self-defense rather than a negative function in in the disease.

The ALS-associated cell is part of our genetic code called “DNA debris.” This DNA contains more than 97 percent of the molecule, but because it does not contain protein, it was previously considered a “shoe.” Today, although this unmatched DNA is considered a dark cell, it is already known to function as an important teaching guide. Among other things, it determines the time organic matter in DNA codeing — those that secrete proteins are activated and deactivated.

Hornstein’s Lab in Weizmann’s Molecular Neuroscience and Molecular Genetics Departments studies neurodegenerative diseases – that is, diseases in which neurons shrink and die. The team focuses on our coding DNA. “This major component, which lacks genetic codeing, has been neglected in the study of the underlying causes of neurodegenerative diseases such as ALS,” Hornstein said. “This is despite the fact that for most cases of ALS, proteins may not be able to explain the symptoms.”

Many people know about ALS thanks to the challenge of Bucket Ice which started the infection a few years ago. This rare disease attacks the motor nerves, nerves that are responsible for controlling the voluntary muscles that are involved in everything from walking to talking and breathing. Gradually the nerves of the body die, eventually leading to respiratory failure and death. One of the symptoms of ALS is inflammation in areas of the brain associated with low-grade neurological disorders, resulting in an immune system in the brain.

Dr. Chen Eitan, who led the study at the Hornstein Laboratory with Aviad Siany, said: “Our brain has a very strong immune system.” “If you have abnormalities, it is called your brain’s immune system microgliawill try to protect you, attacking the path of neurodegeneration. “

The problem is that, in ALS, neurodegeneration becomes severe which activates normal microglial cells in the brain to rise to several levels, turning the toxin. The immune system thus ends up causing damage to brain rose for protection, which resulted in the death of additional nerve cells.

Here is a new study published today in Nature of Neuroscience, come in. Weizmann’s scientists focused on a cell called IL18RAP, which has long been associated with microglia, and discovered that it may contain mutations that reduce the risk of microglia being damaged. “We have found mutations in this cell that reduce inflammation,” Eitan said.

After studying the genes of more than 6,000 patients with ALS and of more than 70,000 people without ALS, the researchers concluded that new mutations reduce the risk of developing ALS by almost five times. It is therefore unlikely that ALS patients will have these protective mutations, and those chronically ill patients who develop them develop the disease almost six years later, on average, than those without a mutation. In other words, the mutation seems to be related to the actual ALS system, reducing the severity of the disease.

To confirm the findings, the researchers used genetic modification technology to introduce protective changes in stem cells from patients with ALS, causing these cells to microglia in the laboratory. They then propagated microglia, with or without immune changes, in the same dishes with fewer bacteria. Microglia carrying protective mutations have been found to be less susceptible to neurons than non-microglia replacement. “Exercise athletes live longer when they are designed with protective microglia, rather than normal,” Siany says.

Eitan noted that the study has a potential impact on ALS research and beyond. “We’ve found a new neuroprotective mechanism,” she said. “Further research could investigate whether adjusting this approach could have a positive impact on patients. In most cases, our research suggests that scientists should not ignore unfamiliar areas of DNA — not only in the study of ALS, but also in the study of other diseases with genetics.


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Learn more:
Chen Eitan et al, The genome-genome series that show that variations in Interleukin 18 Rector Accessory Protein 3′UTR protect against ALS, Nature of Neuroscience (2022). DOI: 10.1038 / s41593-022-01040-6

hint: Genetic mutations are found in code-free DNA to protect the brain from ALS (2022, March 31) retrieved 31 March 2022 from https://medicalxpress.com/news/2022-03-mutations-noncoding- dna-brain-als.html

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