A possible target for the treatment of sleeping sickness has been identified.

Dec 21, 2022 | Current affairs, Featured, Post, Revista Lloseta, Thursday Daily Bulletin, Tradition

Researchers at the Spanish National Research Council have discovered that a protein can destroy the Trypanosoma brucei parasite that causes the disease.

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A team of scientists from the Institute of Parasitology and Biomedicine López-Neyra (IPBLN), belonging to the Spanish National Research Council (CSIC), has identified that a protein called RBP33 can serve as a target for treating sleeping sickness. The absence of this protein generates an accumulation of molecules that kills the Trypanosoma brucei parasite, the organism that causes the disease.

This parasite is part of a group known as trypanosomatids, which cause infectious diseases in humans, such as Chagas disease and Leishmaniasis. Trypanosoma brucei enters the body through the bite of the tsetse fly, an insect that lives in sub-Saharan Africa. This pathology, also known as African trypanosomiasis (ATH), is characterised above all by a state of constant drowsiness that eventually leads to the death of the patient.

The CSIC research, published in the journal Nucleic Acids Research, shows that RBP33 plays an essential role in the destruction of specific RNA molecules: antisense RNA. RNA is the transcript of the genome, i.e. the information of an individual. But there are parts of the genome whose transcription produces potentially dangerous RNA, known as antisense RNA, about which little is known. Researchers have discovered that the protein RBP33 signals antisense RNA so that it can be destroyed.

“We have generated cell lines of these parasites, trypanosomes, where RBP33 is not being produced. Using bioinformatics analysis, we have analysed the transcriptome of these cell lines globally. The absence of RBP33 causes a large amount of antisense RNA molecules to accumulate and the parasite dies,” explains Claudia Gómez-Liñán, first author of the study.

Antonio M. Estévez, CSIC researcher leading this research, adds: “The changes we observed in the transcriptome in the absence of RBP33 are very striking, and are not due to alterations in chromatin accessibility. Rather, RBP33 appears to be involved in marking antisense RNAs for destruction.

Implications for new drugs
Although antisense RNA transcription has been observed in all types of organisms, the RBP33 protein is unique to trypanosomatids. This implies that it may function as a therapeutic target and for further study of these organisms.

The production of new drugs against sleeping sickness, Chagas disease and leishmaniasis could depend on this protein. Gómez-Liñán points out that RBP33 is essential for the survival of the parasite and that it is not present in humans. “This makes it a promising target for therapy,” he says.

For his part, Estévez stresses the interest of these parasites in the study of RNA metabolism. “Trypanosomes emerged very early in the evolution of eukaryotes. The study of their biology at the molecular and cellular level has led to the discovery of new biological phenomena that were first described in these parasites,” he says.

The knowledge in these organisms is very valuable for basic science. All organisms generate antisense RNA that can be harmful, but they also possess proteins that identify this RNA and destroy it.

“Trypanosomes detect antisense RNA differently from other organisms. Our results are therefore valuable for studying the evolution of RNA metabolism in eukaryotes, and may also be useful to better understand these processes in more complex organisms such as humans,” concludes Estévez.

Two IPBLN groups led by Antonio M. Estévez and Elena Gómez-Díaz, respectively, have collaborated in the research.