Identified a possible target to treat sleeping sickness

Sleeping sickness, also called African trypanosomiasis, is caused by two protozoan parasites: Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Both enter the human body through the bite of the tsetse fly, an insect that lives only in sub-Saharan Africa. The disease has several phases of development, but it is characterized above all by producing a state of constant drowsiness that ends up leading to the death of the patient.

These parasites are part of a group known as trypanosomatids, which cause infectious diseases in humans such as Chagas disease or leishmaniasis.

A study carried out by researchers from the López-Neyra Institute of Parasitology and Biomedicine (IPBLN), belonging to the Higher Council for Scientific Research (CSIC) in Spain, has revealed the importance of a protein called RBP33 in Trypanosoma brucei parasites.

The results of the study show that RBP33 plays an essential role in the destruction of certain specific RNA molecules, the antisense RNA. Virtually all of an individual’s information, the genome, is transcribed into another type of information called RNA, although there are parts of the genome whose transcription produces potentially dangerous RNA. These RNAs are known as antisense RNAs and little is known about them. This research has focused on one of the mechanisms that destroy antisense RNA, the RBP33 protein, which signals these RNAs so that they can be specifically recognized and destroyed.

Claudia Gómez-Liñán, first author of the paper, explains the methodology of her research as follows: “We have generated cell lines of these parasites, the trypanosomes, where RBP33 is not being produced. Using bioinformatics analysis, we have analyzed the transcriptome of these “cell lines globally. The absence of RBP33 causes a large amount of antisense RNA molecules to accumulate and the parasite to die.”

Antonio M. Estévez, a CSIC researcher leading this study, explains: “The changes that we observe in the transcriptome in the absence of RBP33 are very striking, and are not due to alterations in the accessibility of chromatin. Rather, RBP33 seems to be involved in marking antisense RNAs for destruction”.

Cultured Trypanosoma brucei cells observed under a microscope. (Photo: IPBLN / CSIC)

Although antisense RNA transcription has been observed in all types of organisms, the RBP33 protein is unique to trypanosomatids. This has two essential implications: its potential as a therapeutic target and its importance for the biological knowledge of these organisms.

Firstly, RBP33 has potential as a therapeutic target for the production of new drugs for diseases such as sleeping sickness, Chagas disease and leishmaniasis, as it is only present in trypanosomatids. Gómez-Liñán highlights 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,” she stresses.

The second implication is of a biological nature. Estévez emphasizes the additional interest that these parasites have as model organisms for the study of RNA metabolism. “Trypanosomes arose very early in the evolution of eukaryotes. The study of their biology at the molecular and cellular level has allowed the discovery of new biological phenomena that were first described in these parasites,” he says. Therefore, knowledge on these organisms is very valuable for basic science. “All organisms continuously generate potentially harmful antisense RNA molecules, and possess specialized proteins that detect, mark, and destroy them. Our work shows that trypanosomes are no exception, but also indicates that they detect antisense RNAs differently from other organisms.” organisms. Our results are therefore valuable for studying the evolution of RNA metabolism in eukaryotes, and may also be useful for better understanding these processes in more complex organisms such as humans.”

Regarding future lines of research, there are two closest objectives: to broaden the knowledge about RBP33 and, then, to continue studying antisense RNA. These parasites can serve as a model for the biological study of the role of antisense RNA.

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

The study is titled “The RNA-binding protein RBP33 dampens non-productive transcription in trypanosomes”. And it has been published in the academic journal Nucleic Acids Research. (Source: CSIC)