Humanized zebrafish could help search for multiple sclerosis therapeutics

Zebrafish serve as a model organism for researchers around the world. It can be used to study important physiological processes that occur in a similar fashion in the human body. Therefore, it is routinely used to search for effective substances against diseases. Researchers from the University of Bonn describe an innovative way to do this. During this process, the fry become a little more “human”. This humanization may make the search for active medicinal substances much more efficient. The results of the pilot study are published in Cell Chemical Biology.

The zebrafish should be known to many aquarium enthusiasts primarily for its pronounced pigmentation. formed only with Eyelash-sized larvae, on the other hand, are still more or less transparent. Therefore, many developmental processes in their bodies can be observed under a light microscope. For this reason, they now serve as model organisms for research groups around the world.

For example, the University of Bonn is studying how zebrafish repair defective nerve tissue. This is also of interest because many of the genes involved in this process are present in humans in a similar fashion. “

Dr. Benjamin Odermatt, Institute for Anatomy, University Hospital Bonn

So, in principle, drugs that enhance repair genes in fish could also work in humans. However, the differences in genetic make-up between fish and humans are often significant. Therefore, larvae may be of limited use in the search for new drugs.

Replacing fish genes with human genes

“That’s why we took a different approach,” explains Professor Evi Kostenis of the Institute of Pharmacobiology, University of Bonn. “For a human gene known to play a role in nerve cell repair, we looked for a zebrafish counterpart. We then excised this fish counterpart and replaced it with the human version. The new genetic material took over the function of the original zebrafish gene. “If we find a substance that accelerates the repair process in fish with human genes, it is highly likely that this will also apply to humans,” says the scientist, who is also a member of the Interdisciplinary Research Area. “Life and Health” at the University of Bonn.

Researchers have demonstrated that this replacement works in a pilot study on the so-called GPR17 receptor. In humans, its overactivation can lead to diseases such as multiple sclerosis (MS). Nerve cells communicate by electrical signals. Their extensions are surrounded by a kind of insulating layer, a lipid-like substance called myelin. Prevents short circuits and greatly speeds up the transmission of stimuli. This protective sheath is produced by specialized cells called oligodendrocytes. These resemble microscopic octopuses. Many long arms extend from the cell body, most of which are composed of myelin. Like insulating tape, these wrap around neuronal processes during brain development. Protective layers usually have a limited lifespan.

Insulating tape dispenser in a crude state

However, in multiple sclerosis, the body’s own immune system destroys the myelin layer. This causes neurological deficits such as speech, vision, and gait. However, there is usually a supply of immature oligodendrocytes in the brain for repair work. When damage occurs, it matures and closes the hole. In multiple sclerosis, this mechanism is disrupted. Many of the donor cells on the cell insulating tape remain in an immature state. The GPR17 receptor appears to be primarily responsible for this: it slows oligodendrocyte maturation when activated by molecular signals.

“Zebrafish also have a GPR17 receptor,” explains Dr. Jesus Gomeza, who led the study with Kostenis and Odermatt. “And there it also regulates the number of oligodendrocytes that mature.” The researchers replaced some of the receptor genes with their human counterparts, the very structures involved in receiving molecular signals. . “We were able to show that this new mosaic gene functions normally in fish larvae,” says Gomeza. A molecule that inhibits the human GPR17 receptor in vitro also promoted the formation of mature modified fish oligodendrocytes.

In the search for new active ingredients, substances are first tested in cell culture. Only individual highly promising candidates are tested in mice or other animal models. But even if they worked there, testing in humans still often ends coldly. It allows us to screen with probability,” explains Benjamin Odermatt. “From our point of view, this is a very promising avenue for drug development.”