Research Summary: In this study, we uncovered essential roles of two actin-like proteins (ALP5a and ALP5b) in regulating DNA segregation and successful male gametogenesis in Plasmodium, and identify them as a potential target for transmission-blocking interventions against malaria.
Author Interview
Aastha Varshney completed her PhD at CSIR-CDRI and is currently exploring postdoctoral opportunities. Her research focuses on parasite biology and molecular mechanisms underlying Plasmodium transmission.
Linkedin: linkedin.com/in/dr-aastha-varshney-386435362
Twitter: @AASTHAVARS001
Instagram: https://www.instagram.com/phd_saint_/
Lab: Dr. Satish Mishra, CSIR-Central Drug Research Institute, Lucknow
Lab social: https://www.instagram.com/phd_resource
What was the core problem you aimed to solve with this research?
Male gametogenesis in Plasmodium is an extremely rapid process involving three swift rounds of DNA replication, reaching an 8N state within minutes. The molecular mechanisms ensuring accurate and timely DNA segregation during this high-speed division were unknown. A key gap was whether these actin-like proteins which were never studied in this context, play a functional role in organizing nuclear division. Our aim was to resolve this fundamental question and understand how these proteins influence parasite development and transmission.
How did you go about solving this problem?
To address this question, we first generated transgenic parasite lines expressing tagged ALP5a and ALP5b to examine their localization and interactions. Independent knockout lines for each ALP were then created using reverse genetics to assess their functional roles. We performed genetic crosses with male- or female-defective mutant lines, which confirmed that both ALPs specifically contribute to male gamete development. High-resolution microscopy allowed us to visualize defects in DNA segregation and protein relocalization during activation. Finally, mosquito transmission assays revealed the impact of ALP loss on oocyst development, establishing their essential role in parasite transmission.
How would you explain your research outcomes (Key findings) to the non-scientific community?
During malaria transmission, the parasite must rapidly divide its DNA to form male gametes. We found two essential Actin like proteins that help correct DNA segregation during male gametogony. In absence of these proteins, DNA segregation is hampered. The compromised male genome—potentially with reduced DNA content—may impair DNA replication during oocyst development and thus block malaria transmission.
This study demonstrates that Plasmodium actin-like proteins ensure accurate DNA segregation during male gametogenesis, highlighting a potential intervention point to disrupt malaria transmission. — Dr. Satish Mishra
What are the potential implications of your findings for the field and society?
Our findings identify critical molecular regulators required for DNA segregation during male gametogony in the mosquito, highlighting potential targets for future transmission-blocking strategies. Understanding these mechanisms provides new directions for designing interventions to reduce malaria spread.
What was the exciting moment during your research?
The most exciting moment was visualizing the dramatic defects in DNA segregation in the knockout parasites and expression of protein relocalizes from nucleus to a microtubule-rich structure, likely the spindle or axoneme during male gametogony.
Paper reference: Varshney A, Pandey E, Nirdosh, Mishra S (2025) Plasmodium actin-like proteins are essential for DNA segregation during male gametogenesis and malaria transmission. PLOS Pathogens 21(11): e1013687. https://doi.org/10.1371/journal.ppat.1013687
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