Fish can help in the search for multiple sclerosis drugs

The zebrafish should be known to many aquarists mainly because of its striking pigmentation. However, the characteristic black and blue stripes, to which the animal owes its name, only form over time. Its eyelash-sized larvae, on the other hand, are more or less transparent. Many development processes in their bodies can therefore be observed under the light microscope. For this reason, they now serve as a model organism for research groups around the world.

“At the University of Bonn, for example, we are investigating how zebrafish repair defective nerve tissue,” explains Prof. Dr. Benjamin Odermatt from the Institute for Anatomy at the University Hospital Bonn. “We are also interested in this because many of the genes involved in this process also exist in humans in a similar form.” Substances that strengthen these repair genes in fish could, in principle, also be effective in humans. However, the differences between the genetic makeup of fish and humans are often significant. Therefore, the larvae are sometimes only of limited use in the search for new medicines. Prof. Odermatt’s research team has now published a study on this topic in Cell Chemical Biology.

Fish gene replaced with human gene

“We therefore took a different approach,” explains Prof. Dr. Evi Kostenis from the Institute for Pharmaceutical Biology at the University of Bonn. “For a human gene that is known to play a role in nerve cell repair, we looked for its counterpart in the zebrafish. Then we excised this counterpart in the fish and replaced it with the human version.” The new genome took over the function of the original zebrafish gene. “If we now find a substance that boosts the repair processes in fish with the human gene, there is a good chance that this will also be the case in humans,” says the scientist, who is also a member of the Transdisciplinary Research Area “Life and Health” at the University of Bonn.

In their pilot study on the so-called GPR17 receptor, the researchers showed that this replacement works. In humans, its overactivation can lead to diseases such as multiple sclerosis (MS). Nerve cells communicate using electrical signals. Their appendages are surrounded by a kind of insulating layer, a lipid-like substance called myelin. It prevents short circuits and also significantly accelerates the transmission of stimuli. This protective covering is produced by specialized cells called oligodendrocytes. These resemble a microscopic octopus: Many long arms, mostly made of myelin, extend from their cell body. During brain development, these wrap around the nerve cell extensions like an insulating tape. Usually the protective layer lasts a lifetime.

Insulating tape dispensers remain immature

In multiple sclerosis, on the other hand, the body’s immune system destroys the myelin sheath. The consequences are neurological disorders, for example when speaking, seeing or walking. But normally there is a reserve of immature oligodendrocytes in the brain for repair work. When damage occurs, they mature and patch the hole. In multiple sclerosis, this mechanism is disrupted – many of the cellular insulating tape donor cells remain in their immature state. The main culprit seems to be the GPR17 receptor: when activated by a molecular signal, it slows down the maturation of the oligodendrocytes.

“Zebrafish also have a GPR17 receptor,” explains Dr. Jesus Gomeza, who led the study with Kostenis and Odermatt. “And there it also regulates how many oligodendrocytes mature.” The researchers have now replaced part of the receptor gene with its human counterpart – precisely the structure that is responsible for receiving molecular signals. “We were able to show that this new mosaic gene functions normally in the fish larvae,” says Gomeza. A molecule that inhibits the human GPR17 receptor in the test tube also boosted the formation of mature oligodendrocytes in the modified fish.

When searching for new active ingredients, substances are first tested in cell cultures. Only individual, promising candidates are then tested in mice or other animal models. But even if they work there, tests on humans often end in a sobering way. “With humanized zebrafish larvae, many substances can be screened quickly and with a high chance of success, since the target genes come from humans,” explains Benjamin Odermatt. “In our view, this is a very promising avenue for drug development.”