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When people think of the link between genes and disease, they often envision something that works like a switch: When the gene is normal, the person carrying it does not have the disease. If it is mutated, a switch is flipped, and then they have it.
But it’s not always that simple. Genes linked to the disease often have different degrees of activation or deactivation. In these cases, there is a tipping point: with only a gradual biological change around a critical threshold, a person can go from having no symptoms to serious illness. The latest research on this topic from the Salk Institute has implications for the study and treatment of the underlying causes of amyotrophic lateral sclerosis (ALS) and other neurological and psychiatric disorders. The work, published in Neuron on August 26, 2021, could also apply to a wide range of diseases involving changes in the levels of gene expression, such as cancer.
“This is increasingly becoming a very interesting new direction for ALS research,” says Professor Salk Samuel Pfaff, lead author of the article. “Our study is very revealing about how gene regulation occurs in neurons. Although our experiments were performed in mice, we believe these results will apply to humans as well.”
A handful of genes have been found in patients that are associated with ALS, a motor neuron disease that leads to paralysis. What many of these genes have in common is that they are linked to the making of microRNAs (miRNAs) – regulatory molecules that act as brakes to reduce protein production. In the first part of this research, the team performed a systematic review of previous studies that profiled microRNA levels in patients with ALS. They found that in all of the studies, the same microRNA, called miR-218, continued to show up as inferior, but not completely lost, in people with ALS. They decided to investigate why particular levels of miR-218 are important for motor neurons to do their jobs normally.
In a mouse model of ALS, Salk researcher Neal Amin, now a clinical researcher and postdoctoral researcher at Stanford University, devised a strategy to finely lower levels of miR-218 in a controlled manner in order to study the effects on muscle control of motor neurons. function. Amin discovered that there is a critical threshold between 36% and 7% of normal levels which leads to muscle paralysis and death. Above 36%, neuromuscular junctions are normal and healthy; below 7 percent, neuromuscular deficits are fatal. The rest of the study was to try to understand why this was the case.
It turns out that miR-218 regulates the function of about 300 different genes. Many of them code for proteins related to the way motor neurons develop axons and send signals to muscles. Once the miR-218 levels fell below 36%, the way these neurons could signal to the muscles decreased dramatically. The researchers used cutting-edge laboratory tools to determine how miR-218 affected various genes.
“Instead of acting like a simple switch, the miR-218 molecule is like a conductor of 300 musicians playing together,” says Amin. “Instead of gradually telling all players to lower the volume of their instruments in unison, this tells some musicians to play more slowly and others to stop completely. It has much more dynamic control and complex on gene function than we had ever appreciated before. “
The researchers say the ability to study this fine-tuning in animal models will allow them to learn much more about how genetic mutations that reduce gene expression put patients at risk for developing brain disorders. This could eventually lead to new treatments that get to the heart of the biological changes that lead to the disease. The research not only has implications for ALS, but also for other diseases of the nervous system, including schizophrenia, which has also been associated with changes in the level of microRNA expression.
“We believe these processes can also take place in other diseases related to genes and aging, including cancer,” says Pfaff, Benjamin H. Lewis Chair at Salk. “Having a new way to create animal models of the onset and progression of genetic diseases will allow us to understand the underlying mechanisms and better understand these complex activities. “
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