Activation of calpains, calpastatin and spectrin cleavage in the brain during the pathology of fatal murine cerebral malaria

Shukla, Meena; Rajgopal, Yadavalli; Babu, Phanithi Prakash

doi:10.1016/j.neuint.2005.09.001

Cited by 24 publications

(22 citation statements)

References 31 publications

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“…Some of these genes also have been implicated in neuronal death in neurological diseases (11,17,60), including CM (33,56). A number of protease inhibitors were expressed on the arrays, including CTLA-2␣ (22), and may represent a host mechanism to limit the damage mediated by proteases, particularly since these proteolytic processes can lead to development of intracerebral hemorrhaging (63), which is an invariable finding in human and murine CM.…”

Section: Discussionmentioning

confidence: 99%

Predominance of Interferon-Related Responses in the Brain during Murine Malaria, as Identified by Microarray Analysis

2008

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Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. We examined global gene expression patterns during fatal murine CM (FMCM) and noncerebral malaria (NCM) by microarray analysis. There was differential expression of a number of genes, including some not yet characterized in the pathogenesis of FMCM. Some gene induction was observed during Plasmodium berghei infection regardless of the development of CM, and there was a predominance of genes linked to interferon responses, even in NCM. However, upon real-time PCR validation and quantitation, these genes were much more highly expressed in FMCM than in NCM. The observed changes included genes belonging to pathways such as interferon signaling, major histocompatibility complex processing and presentation, apoptosis, and immunomodulatory and antimicrobial processes. We further characterized differentially expressed genes by examining the cellular source of their expression as well as their temporal expression patterns during the course of malaria infection. These data identify a number of novel genes that represent interesting candidates for further investigation in FMCM.Malaria is a devastating disease affecting developing countries in the tropical and subtropical regions of the world. Cerebral malaria (CM), a severe manifestation of Plasmodium falciparum infection, can lead to neurological complications and death (64). Murine models of malaria are important tools for studying the pathogenesis of malaria, with numerous clinical and histopathological similarities between human and murine malaria having been described (19). Comparisons between fatal murine CM (FMCM) and noncerebral malaria (NCM) provide valuable insights into the pathogenesis of CM.A number of significant changes in the murine brain that characterize CM have been described, including breakdown of the blood-brain barrier (62), redistribution and activation of glia (31,32,34), apoptosis of endothelial cells and astrocytes (46,47), metabolic changes (44, 48), and distinct patterns of chemokine gene expression (38).A recent approach to identifying novel changes within the brain during CM is to profile gene expression changes using microarray technology (9, 30). Microarray studies can generate a plethora of data that pinpoint involvement of unknown or poorly characterized genes, stimulating investigation of their biological functions. Some studies have used microarrays to examine global gene expression patterns during murine malaria, defining gene expression profiles that are associated with susceptibility or resistance to murine CM (26, 27), identifying genes in the brain that discriminate between different outcomes of Plasmodium infection (5), or describing trends in gene expression within the brain (55). Studies on the spleen have been performed to find genes that differentiate between cerebral and noncerebral (55) and between lethal and nonlethal (52) forms of murine malaria. Microarrays also have been used to examine Plasmodium infection in humans (14, 41) and monke...

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Section: Discussionmentioning

confidence: 99%

Predominance of Interferon-Related Responses in the Brain during Murine Malaria, as Identified by Microarray Analysis

2008

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“…Moreover, several studies have shown CHOP playing a role as a pro-apoptotic molecule induced by ER stress [16,17,23] and earlier studies from our laboratory have shown that the pathology of ECM manifests neuronal apoptosis [10,11,12,13]. To substantiate our results, we checked the levels of pro-apoptotic proteins like BAX, caspase-3, active caspase-7, caspase-12 and anti-apoptotic BCL-2.…”

Section: Resultsmentioning

confidence: 99%

“…C57BL/6J mice infected with PbA develop neurological signs and symptoms typical of human CM and die within 6-12 days after infection [3]. Studies with this model have identified the upregulation of several pro-apoptotic mediators as major cause of neuronal cell death during the course of infection [8,9,10,11,12,13]. An overwhelming evidence points out the activation of inflammatory pathways, upregulation of cytokines such as tumour necrosis factor α, γ-interferon, interleukins 1, 6 and 8 and PRBC sequestration during the pathophysiology of CM [4].…”

Section: Discussionmentioning

confidence: 99%

“…Further, a direct proof of evidence linking disturbances in neuronal calcium homeostasis to PERK activation is lacking in the ECM model. However, supporting evidence in the form of calpain activation owing to altered calcium homeostasis in pathological manifestation of the disease is well established [12]. Activation of PERK leads to eIF2α phosphorylation, thereby shutting off mRNA translation and reducing the protein load on the ER.…”

Section: Discussionmentioning

confidence: 99%

“…The pathological features of the fatal stage include PRBC and monocyte adhesion to cerebral vascular endothelial cells, oedema, petechial hemorrhages, glial activation and neuronal cell death in the central nervous system [5,6,7,8,9]. The mechanisms leading to cell death are complex, and several pathways have been implicated, including mitochondrial dysfunction, calcium-activated kinases, phosphatases and proteases, caspases and c-Jun N-terminal kinases (JNK) [8,10,11,12,13]. Though the events central to tumour necrosis factor and interleukin are activated during ECM [14], to our understanding no reports exist on the role of endoplasmic reticulum (ER) stress proteins during cell death in the brain.…”

Section: Introductionmentioning

confidence: 99%

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Endoplasmic Reticulum Stress and Neurodegeneration in Experimental Cerebral Malaria

Anand¹,

Babu²

2013

Neurosignals

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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.

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SNPs in CAST are associated with Parkinson disease: A confirmation study

Allen

Satten

2010

American J of Med Genetics Pt B

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Using data from the National Institutes of Neurological disease and Stroke's (NINDS) study of Parkinson disease (PD), we recently reported that single nucleotide polymorphisms (SNPs) in a region containing the Calpastatin (CAST) gene were associated with PD. Here we follow up this finding with an analysis of the Center for Inherited Disease Research's (CIDR) genome-wide association study in familial PD. After adjusting for population stratification and multiple testing, we find a significant association (p=0.0167) between PD and SNP rs1559085 in CAST. These findings confirm CAST/PD associations in a second, independent, dataset and suggest that CAST be prioritized for further investigation.

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Activation of calpains, calpastatin and spectrin cleavage in the brain during the pathology of fatal murine cerebral malaria

Cited by 24 publications

References 31 publications

Predominance of Interferon-Related Responses in the Brain during Murine Malaria, as Identified by Microarray Analysis

Predominance of Interferon-Related Responses in the Brain during Murine Malaria, as Identified by Microarray Analysis

Endoplasmic Reticulum Stress and Neurodegeneration in Experimental Cerebral Malaria

SNPs in CAST are associated with Parkinson disease: A confirmation study

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