Endoplasmic Reticulum Stress and Neurodegeneration in Experimental Cerebral Malaria

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.

Endoplasmic Reticulum Stress and Unfolded Protein Response in Infection By Intracellular Parasites

“…Cerebral malaria is one of the most serious complications of Plasmodium infection. An experimental murine model of cerebral malaria, induced by the infection of susceptible mice with Plasmodium berghei , has been used to examine the role of ER stress response in modulating neuronal cell death induced by this parasite [ 62 ]. The brains of infected and uninfected mice were analyzed by western blotting and immunohistochemistry, showing the activation of the three ER stress sensors ATF6, PERK and IRE1α.…”

Expedition into Taurine Biology: Structural Insights and Therapeutic Perspective of Taurine in Neurodegenerative Diseases

“…The activation of signaling cascades is mediated by dissociation of glucose regulated protein-78 (GRP-78) from PERK, IRE1 and ATF6,which initiates downward signaling in order to overcome ER stress. Under prolonged stress conditions, UPR fails in restoring the correct folding of proteins, and as such directs cells to apoptosis via the activation of pro-death components, such as the C/EBP homologous protein (CHOP), Caspase 12 and JNK [215][216][217]. Taurine is believed to be involved in restoring current folding of proteins, either through reduction in oxidative stress or through providing suitable osmotic conditions for proteins to fold [218].…”

Selected terpenoids from medicinal plants modulate endoplasmic reticulum stress in metabolic disorders

“…Even though a substantial amount of people die from the disease annually, the pathogenesis in humans remains largely unstudied because of experimental analysis only occurring post-mortem. [205] In recent years, a murine model has been used to study the pathogenesis of cerebral malaria after infected with P. berghei. The murine model is used to study cerebral malaria because it displays symptoms typical of humans cerebral malaria.…”

“…The contraction and progression of cerebral malaria develops as a result of complications after the infection of Plasmodium falciparum . Even though a substantial amount of people die from the disease annually, the pathogenesis in humans remains largely unstudied because of experimental analysis only occurring post‐mortem [205]. In recent years, a murine model has been used to study the pathogenesis of cerebral malaria after infected with P. berghei .…”

“…At the stage, where the infection results in cell death, several signalling pathways have been implicated, including mitochondrial dysfunction, activation of calcium‐dependent and independent kinases (e.g. JNK), caspases and recently ER stress [205–207]. Anand and Babu[205] illustrated the role of ER stress in neuronal cell death in mice infected with P. berghei .…”