Introduction

Researchers have identified a genetic variation, found in 3% of the world’s population, that increases the risk of inflammation through a mechanism called “explosive cell death.”

Implications for Disease Development

This research may shed light on why some people are more likely to develop diseases such as inflammatory bowel disease or have severe reactions to bacterial infections such as salmonella.

Understanding Cell Death

Every minute, millions of cells in our bodies die intentionally. Cell death is an important process that protects our body from disease by removing unwanted, damaged or dangerous cells and preventing the spread of viruses, bacteria and even cancer.

The researchers say that while there are different types of cell death, “explosive cell death,” known as necrosis (or necrosis) of cells, is characterized by its brutality as cells essentially explode, alarming other cells in the body so they can respond. them. presence of invaders, but if left unchecked, this can lead to an excessive inflammatory response.

The Genetic Error

Recently, a team of researchers identified a genetic error that prevents cell necrosis. Researchers estimate that this genetic variant, a single-base change in the gene that codes for the MLKL protein, may be found in up to 3% of people.

Researchers say that MLCL is necessary to stimulate the death of dead cells, a natural process that protects the body from infection. But for 3% of the world’s population, it can go wrong and cause tissue damage.

Potential Disease Associations

Researchers have not yet linked the MLKL gene to any specific disease, although after identifying its effects in cell cultures and animal models, a study conducted by the Walter and Eliza Hall Health Research Institute (WEHI) in Melbourne, Australia, says it may increase the risk of infection people with inflammatory diseases such as diabetes and gastritis, or more severe reactions to infections in combination with other genetic and environmental factors.

“Every piece of information like this helps us make personalized medicine more realistic,” explained Dr. Sarah Garnish, a cell biologist at the Walter and Eliza Hall Center for Medical Research who led the study. She added: “In most of us, the MLKL gene turns off when the body tells it to stop, but 2-3 percent of people have a form of MLKL that is less responsive to stop signals. Although 2-3 percent do not respond to stop signals.” seems like a lot when you take into account the world’s population. “This means that millions of people carry a copy of this altered gene.”

The S132P Variant

The genetic variant is named S132P to replace serine (an organic compound) with a proline molecule, consisting of 132 amino acids in the MLKL protein.

In previous work, a team led by Joan Hildebrand, a cell biologist at the Walter and Eliza Hall Institute for Medical Research, identified S132P as the third most common human variant of MLKL. They also showed that it gradually accumulates in cell membranes until these overloaded cells burst, filling with inflammatory molecules called cytokines.

Distribution in Populations

In this study, the researchers revisited the global genome sequence database and found that S132P variants are still absent in people of East Asian descent and are rare in African and Hispanic populations; It is more common in people of Ashkenazi Jewish descent.

They also identified two carriers in the Australian Registry of People with Immune Disorders, but wanted to better understand how S132P affects inflammatory responses before drawing any conclusions.

Lab Experiments and Mouse Models

Laboratory experiments have shown how S132P promotes the accumulation of the MLKL protein in cell membranes, promoting necrosis. Cells with this variant were also able to bypass chemical instructions and block MLKL activity while retaining their ability to self-detonate.

Moreover, mice engineered to carry two dysregulated copies of MLKL, similar to the human variant, showed impaired immune responses: their defense systems against pathogens were compromised due to a widespread deficiency of immune cells, with the precursors of these cells showing “increased propensity to to cell death” when being compressed.

Most people do not carry two dysregulated copies of MLKL, and the mice in the study that had only one copy did not have the same risk of necrosis. So this doesn’t necessarily mean that people with this mutation are doomed to poor health.

Further Research Needed

Clearly something is going on, but researchers still have a lot of work to do to understand how the genetic makeup of MLKL may contribute to inflammatory conditions in people.

The study was published in the journal Nature Communications.

Source: Alert Sign