title: 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.
authors.affiliation: Department of Biotechnology, School of Life Sciences, University of Hyderabad, Hyderabad, India.
authors.forename: Sripada Santosh
authors.initials: SS
authors.lastname: Anand
authors.forename: Phanithi Prakash
authors.initials: PP
authors.lastname: Babu
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D016779:Malaria, Cerebral / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology