Related Experiment Video
Updated: May 22, 2026
In Vivo Tracking of Edema Development and Microvascular Pathology in a Model of Experimental Cerebral Malaria Using Magnetic Resonance Imaging
Published on: June 8, 2017
Endoplasmic reticulum stress and neurodegeneration in experimental cerebral malaria
Sripada Santosh Anand1, Phanithi Prakash Babu
1Department of Biotechnology, School of Life Sciences, University of Hyderabad, Hyderabad, India.
Abstract:
Experimental cerebral malaria (ECM) resulting from Plasmodium berghei ANKA (PbA) infection in mice results in neuronal cell death. However, the precise mechanisms leading to neuronal cell death in ECM have not been fully elucidated. In the present study, we report the presence of endoplasmic reticulum (ER) stress markers and activation of the unfolded protein response (UPR) in the brain during the pathogenesis of ECM. Specific findings included activation of PKR-like ERkinase, inositol-requiring enzyme 1 and cleavage of activating transcription factor (ATF) 6 indicating the activation of all three major arms of the UPR. Further, we found changes in the protein levels of phosphorylated eukaryotic initiation factor α (p-eIF2α), ATF4, growth arrest and DNA damage-inducible protein 34, B cell lymphoma protein 2 (BCL-2), BCL-2-associated X protein, caspase-7, cleavage of caspase-3, and caspase-12. Our results demonstrate that ER stress-induced neuronal cell death in PbA-infected mice is associated with the expression of the pro-apoptotic molecule CHOP and downregulation of anti-apoptotic ER quality control molecules binding immunoglobulin protein, calreticulin and calnexin. Further CHOP was found to be localized in neurons and plays an essential role in neuronal cell death as revealed by our Fluoro-Jade B double staining. These results implicate an imbalance between ER stress-mediated pro-apoptotic and anti-apoptotic/survival signalling as a critical determinant of neuronal cell death in ECM.
Insights
Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) contribute to brain cell death in experimental cerebral malaria (ECM). This involves pro-apoptotic signaling, highlighting ER stress as a key factor in ECM pathogenesis.
Area of Science:
- Neuroscience
- Immunology
- Cellular Biology
Background:
- Experimental cerebral malaria (ECM) in mice, caused by Plasmodium berghei ANKA (PbA) infection, leads to neuronal cell death.
- The exact mechanisms driving neuronal cell death in ECM remain unclear.
Purpose of the Study:
- To investigate the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the pathogenesis of ECM.
- To elucidate the molecular mechanisms underlying ER stress-induced neuronal cell death during PbA infection.
Main Methods:
- Analysis of ER stress markers and UPR activation in the brains of PbA-infected mice.
- Assessment of protein levels associated with UPR signaling, apoptosis, and ER quality control.
- Immunohistochemical localization of the CHOP protein in neurons using Fluoro-Jade B staining.
Main Results:
- Activation of all three major arms of the UPR (PKR-like ER kinase, inositol-requiring enzyme 1, ATF6) was observed in the brain during ECM.
- Changes in key proteins involved in ER stress, apoptosis (e.g., p-eIF2α, ATF4, BCL-2 family, caspases), and ER quality control were detected.
- Pro-apoptotic CHOP expression in neurons correlated with neuronal cell death, while anti-apoptotic ER proteins were downregulated.
Conclusions:
- ER stress and UPR activation are significant contributors to neuronal cell death in experimental cerebral malaria.
- An imbalance between pro-apoptotic and anti-apoptotic signaling pathways mediated by ER stress is critical in ECM-induced neurodegeneration.
- CHOP plays an essential role in neuronal apoptosis during ECM.
