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May 31 2025
4Malaria continues to be a major global health challenge, with Plasmodium falciparum responsible for the most severe and fatal cases. The parasite’s growing resistance to existing treatments highlights the pressing need for new therapeutic targets. A groundbreaking study led by the Nanomalaria research group, a collaboration between the Institute for Bioengineering of Catalonia (IBEC) and the Barcelona Institute for Global Health (ISGlobal), uncovers a potential weak point in the parasite's biology—its protein regulation system.
Published in Frontiers in Cellular and Infection Microbiology, the study demonstrates how disrupting the parasite’s internal balance of protein folding and degradation, a system known as proteostasis, could impair its survival. Researchers focused on the overexpression of a particular segment of an intrinsically disordered protein called PfUT, a ubiquitin-protein ligase prone to misfolding. This induced disruption led to protein aggregation, significantly hindering parasite growth.
Protein aggregation involves the clumping of misfolded or unstable proteins into insoluble clusters. In humans, such processes are linked to neurodegenerative diseases like Alzheimer’s and Parkinson’s. Cells typically combat aggregation through molecular chaperones and the proteasome system, which collectively maintain proteostasis by regulating protein synthesis, folding, and breakdown.
Intriguingly, P. falciparum maintains a robust proteostasis network to cope with environmental stress throughout its life cycle—inside both its mosquito vector (Anopheles species) and human hosts. However, its proteins are unusually prone to aggregation. This apparent contradiction may stem from an evolutionary trade-off: while a streamlined genome and proteome enhance efficiency, the inherent instability of many proteins, especially those with disordered regions, may offer adaptive benefits under stress, such as febrile episodes in humans or oxidative stress in infected cells.
The study explored whether artificially increasing the levels of the aggregation-prone PfUT protein would overload the parasite’s protein control mechanisms. Indeed, overexpression of a disordered segment of PfUT triggered proteotoxic stress and suppressed parasite growth. Yet, despite this disruption, the parasite was not completely eliminated, suggesting it possesses mechanisms to manage a high burden of misfolded proteins.
“This overexpression unbalanced the parasite’s delicate proteostasis, leading to a measurable decline in its proliferation,” noted Yunuen Avalos-Padilla, lead author of the study. “Still, the parasite managed to survive, showcasing its ability to endure considerable proteotoxic stress.”
The findings highlight an exploitable vulnerability in the parasite: its sensitivity to disruptions in protein folding and degradation. Future antimalarial therapies could potentially leverage this by further enhancing protein misfolding or inhibiting the parasite’s response to aggregation, thereby tipping the balance beyond recovery.
As study co-author Fernàndez-Busquets explained, “We’ve identified a fundamental flaw in Plasmodium falciparum’s protein regulation that could serve as a novel target for antimalarial intervention. A deeper understanding of its proteostasis system could unlock promising new treatment avenues.”
While the results are promising, further research is necessary to translate these insights into clinical solutions. Scientists must determine how these vulnerabilities behave across different stages of the parasite's life cycle and ensure that any new compounds developed are both effective and safe.
By turning the parasite’s own protein machinery against it, this research could mark a new frontier in the fight against malaria—offering hope for more effective treatments in the face of rising drug resistance.
Source:https://phys.org/news/2025-05-disrupting-malaria-parasite-protein-key.html
This is non-financial/medical advice and made using AI so could be wrong.
