Researchers from the Institute for Bioengineering of Catalonia (IBEC) and the Barcelona Institute for Global Health (ISGlobal), with laboratories at the Barcelona Science Park, have led a study highlighting protein aggregation as a potential target for discovering new ways to reduce the viability of Plasmodium falciparum, the main parasite responsible for the most severe form of malaria. The study, published in the journal Frontiers in Cellular and Infection Microbiology, could pave the way for new antimalarial strategies aimed at the parasite’s internal protein-folding machinery.

Researchers from the Nanomalaria research group at the Institute for Bioengineering of Catalonia (IBEC) and the Barcelona Institute for Global Health (ISGlobal) induced the overexpression of a specific segment of an intrinsically disordered protein, which significantly affected the growth of the parasite.

Central to this investigation is the concept of protein aggregation, which refers to the accumulation of misfolded or unfolded proteins into insoluble clusters. In humans, this process is associated with several neurodegenerative diseases, including Alzheimer’s and Parkinson’s, where aggregated proteins disrupt cellular functions and lead to cell death. Protein aggregation is typically counteracted by molecular chaperones and proteasomal systems that maintain proteostasis—an essential cellular balance of protein synthesis, folding, and degradation.

In Plasmodium falciparum, however, the scenario is particularly intriguing. On the one side, the parasite’s encodes a robust proteostasis network adapted to survive the intense metabolic changes and stress conditions it encounters during its life cycle, both inside its vector, mosquitoes from the genus Anopheles, and the human host.

However, and contradictorily, proteins of the parasite are highly prone to aggregation. Despite its relatively small genome and efficient proteome, the high propensity to protein aggregation in this organism may reflect a fine-tuned evolutionary trade-off between functionality and instability. This property may confer the parasite specific adaptive advantages such as aiding in protein protection or facilitating the formation of stress-related aggregates that help it survive in hostile environments, such as fever in human host and oxidative stress in infected cells.

In this sense, it possesses a relatively high proportion of proteins with intrinsically disordered regions —such as the ubiquitin-protein ligase, PfUT— which are generally more prone to misfolding and aggregation under stress.

A potential Achilles’ heel in malaria parasites

This complex proteomic scenario led the researchers to explore whether an induced increase of a highly abundant and aggregation-prone protein like PfUT could shift the parasite’s proteome towards an aggregation state surpassing its proteostasis control machinery, leading to a decrease in its viability.

“By overexpressing a disordered segment of PfUT in P. falciparum, we disrupted this fragile balance, triggering proteotoxic stress and leading to reduced parasite growth. However, despite the observed alterations in proteostasis, the parasites were not killed by the increased aggregation of this particular protein, showing their capacity to control a highly aggregation-prone proteome”, explains Yunuen Avalos-Padilla, first author of the work.

This discovery identifies a novel and potentially exploitable aspect of the parasite’s biology: its susceptibility to disruptions in protein aggregation control. Therapeutic strategies that amplify protein misfolding of certain key proteins or block the parasite’s ability to respond to aggregation could therefore offer a powerful new line of attack.

In words of Xavier Fernàndez-Busquets, “this study not only highlights a key vulnerability in Plasmodium falciparum‘s internal protein management system but also positions protein aggregation control as a promising target for antimalarial intervention. By deepening our understanding of the parasite’s proteostasis mechanisms, we may unlock new avenues for combating one of the world’s most persistent infectious diseases”.

Nonetheless, moving from laboratory findings to clinical application requires further work. Future studies will need to elucidate the precise molecular interactions involved and determine whether similar vulnerabilities exist in different life stages of the parasite. Additionally, any compounds developed to exploit this mechanism must be carefully assessed to ensure selectivity and safety.

» Article de reference: Lucía Román-Álamo, Yunuen Avalos-Padilla, Inés Bouzón-Arnáiz, Valentín Iglesias, Jorge Fernández-Lajo, Juan M. Monteiro, Luis Rivas, SHOW ALL (15 AUTHORS), Xavier Fernàndez-Busquets. Effect of the aggregated protein dye YAT2150 on Leishmania parasite viability. Antimicrobial Agents and Chemotherapy (2024). DOI: 10.1128/aac.01127-23

» Link to the news: IBEC website [+]