Key protein in trisomy 21 inhibited A new approach to a potential active agent

Researchers from the Departments of Biology and Pharmacy at TU Braunschweig are working together on genetic models for trisomy 21, Down’s syndrome. In experiments with zebrafish, they have now been able to manipulate a key gene.

Trisomy 21, or Down syndrome, is caused by an extra copy of chromosome 21 in the genome. A key factor is the DYRK1A gene, which codes for the DYRK1A protein. It primarily affects the nervous system, which is particularly inaccessible to active agents. Researchers at TU Braunschweig are working on an inhibitor for the DYRK1A protein in the Infections and Active Agents research area. Initial tests on zebrafish suggest that this could be used to curb these congenital nerve cell defects.

Can small zebrafish from the subtropics be affected by Down’s syndrome? At first glance, the answer is no. Although humans and zebrafish have a lot of genetic overlap, they do not have the same number of chromosomes or the same chromosomes. However, a closer look reveals that some of the genes involved in trisomy 21 are present in both. For example, DYRK1A.

To simulate the effects of trisomy 21 in the nervous system of zebrafish larvae, Dr. Astrid Buchberger of Professor Reinhard Köster’s Cellular and Molecular Neurobiology research group specifically overactivated the DYRK1A gene. Although she could not reproduce the extra copy of the gene, she was able to simulate the overactivity of three DYRK1A genes instead of the two normally present in trisomy 21. A contrast agent makes the selected nerve cells visible under the microscope. Zebrafish larvae are almost transparent, so the coloured nerve cells can be observed even during development.

Dr. Astrid Buchberger: “The genetically modified nerve cells were less well connected, less complex and more densely packed. This may explain why these zebrafish larvae swim more slowly and cover significantly shorter distances. However, it remains to be seen to what extent the zebrafish show symptoms of trisomy 21. Naturally, there are no zebrafish with real trisomy 21 to study as a comparison group.

Precision against side effects

Dyrk1A is not only being studied by biologists at the Institute of Zoology, but also at the Institute of Medicinal and Pharmaceutical Chemistry. Professor Conrad Kunick’s working group has synthesised an inhibitor of the DYRK1A protein called KuFal194. A computer simulation shows that this inhibitor can be precisely integrated into the crucial site of DYRK1A. Maren Flaßhoff, doctoral student in the research group: “It is amazing how precisely the inhibitor can bind to DYRK1A. In both the zebrafish and the human protein, KuFal194 only blocked what it was supposed to block in the computer simulation.

It is still unclear whether such a potential active agent also reaches the brain. This is suggested by the fact that the DYRK1A-overactive nerve cells of zebrafish larvae raised in water containing the inhibitor were virtually indistinguishable from those of other larvae. It is therefore likely that the inhibitor binds the excess Dyrk1A. There were no obvious side effects in the treated zebrafish larvae. Further studies could provide a starting point for the development of an active agent.

“Such an active agent would have to be taken as soon as possible after birth. However, it will take many years of further research to determine whether such an active agent can be developed at all. For the time being, these are promising results from basic research,” says Professor Reinhard Köster.