Promising potential target for TSC treatment

MIBMIK researchers, conducting an in-depth study of a zebrafish model of tuberous sclerosis complex (TSC), have unexpectedly discovered a new potential therapeutic target that could potentially improve the effectiveness of existing therapies and the quality of life of TSC patients.


Tuberous sclerosis is a rare disease. One in 5000 people is born with a mutation in TSC1 or TSC2 genes, which leads to excessive activity of the enzyme called mTOR and consequent serious changes in cell metabolism. Tuberous sclerosis is a disease of the whole organism, but numerous pathological changes affect the brain and its functioning. Characteristic features of TSC include the formation of benign brain tumors (so-called cortical tubers), changes in the white matter of the brain or abnormalities in the course of connections between hemispheres. As a result, people with TSC have epilepsy, often resistant to treatment. In addition to epilepsy, some of them suffer from TSC-associated neuropsychiatric disorders (TANDs). The treatment of TSC involves the administration of symptom-directed or mTOR-correcting drugs. Still, however, the effects of treatment vary greatly from patient to patient and the need to find additional therapies is current. What is more, even though TSC is a rare disease, its symptoms such as epilepsy, autism or mood swings are not. Therefore, TSC, as a disease of known etiology, is considered to be a disease that can help to understand the mechanisms of these phenomena and to find remedies effective not only for TSC.


There are many animal models of TSC, created mainly based on genetic modification of mice. However, zebrafish (Danio rerio) without Tsc2 is also available. It would seem that it is challenging to study human diseases, especially those affecting the brain, using such a distant evolutionary model. However, zebrafish is not as far away as we think and has many features that allow for a comprehensive study of the mechanisms of brain development, which is very difficult in placentals. These features include the fact that the embryonic development of zebrafish takes place outside the mother’s body and the Danio larvae are transparent so that the migration of nerve cells or their activity in the developing fish can be analyzed in real-time. Besides, zebrafish, living in shoals and contacting other members of the stock, has a highly developed social behavior that can be analyzed automatically in a high-throughput way. Therefore, a few years ago, it was decided to introduce this research model to the IIMCB under the European grant "FishMed" to study a variety of human disorders, including TSC.


The team of Prof. Jacek Jaworski as part of the “FishMed” grant and then as part of the funds obtained by Dr Justyna Zmorzyńska from the National Science Centre decided to check how much zebrafish TSC model can be used for research on this disease. Earlier works indicated that fish deprived of TSC2 suffer from abnormal cell positioning in the brain as well as seizures. However, previous studies did not refer to the formation of long-distance connections or whether fish deprived of TSC2 may have behavioral problems similar to those in human disease. The answer to these questions was the aim of the research of Dr. Zmorzyńska and Prof. Jaworski and their collaborators, mainly a promising Ph.D. student Magda Kędra. As a result, the team succeeded in demonstrating that in the studied model, interhemispheric connections in the brain are disturbed. These fish were also characterized by a higher level of anxiety. Finally, the team was also able to show that TSC zebrafish may be a convenient model of a type of epilepsy called absence seizures. However, the most exciting discoveries of the team were the result of searching for the molecular mechanism of the observed changes. Some of the disease-like symptoms could be "cured" with standard drugs used in the clinic such as vigabatrin or rapamycin. However, it turned out that in the case of some anatomical and behavioral manifestations of “fish” TSC, administration of TrkB protein inhibitors, so far not associated with TSC pathology, gave the best results. Moreover, only TrkB inhibitors corrected hemispherical connections as well as reduced seizures and anxiety levels. This suggests that subtle changes in the connectivity of different brain regions lie at the root of TANDs. On the other hand, it is potentially more important that TrkB can be a new therapeutic target.


Although research on TSC zebrafish, the results of which have just appeared in the prestigious journal Proceedings of the National Academy of Sciences (Kedra et al., 2020), do not provide answers whether TrkB inhibitors can be used in human therapy, the findings made in the Laboratory of Molecular and Cellular Neurobiology provide a solid argument for further preclinical research in this direction, e.g. using nerve cells obtained from patients by reprogramming cellular fate and other animal models.


Full article: https://www.pnas.org/content/117/4/2170