c-Jun N terminal kinases (JNK) are activated in the brain during the pathology of experimental cerebral malaria

Experimental cerebral malaria (ECM) resulting from Plasmodium berghei ANKA (PbA) infection in C57BL/6J mice manifests cell death in the brain. However, the precise molecular and biochemical mechanisms regulating cell death during ECM remains unknown. In this study we have examined, the role of a stress activated protein kinase called c-Jun N terminal kinase during the pathology of ECM. We report in this study, for the first time the activation of all key elements in the JNK pathway like p-MKK4, p-JNK and p-c-Jun in mouse brain during ECM. Concomitant with such activation was the up regulation of p-JNK and its translocation into the nucleus leading to the phosphorylation of its major substrate c-Jun. These observations show the neuronal induction of p-JNK and its critical role as a mediator in neuronal cell death during ECM.

Research highlights▶ Investigated the activation of JNK pathway in the mouse brain following infection with PbA. ▶ This is the first evidence of JNK mediated neuronal cell death in experimental cerebral malaria. ▶ Phosphorylated forms of all the key elements in the JNK signal transduction pathway, viz., MKK4, JNK, and c-Jun were significantly upregulated in infected mouse brains compared to uninfected controls. ▶ Immunostaining of control and terminally ill mouse brain sections with p-JNK, revealed robust increase of p-JNK positive cells indicating activation of JNK in infected brains. ▶ Double labeling experiments revealed that Flouro-Jade B positive cells are also positive for p-JNK, implying that p-JNK plays a crucial role in mediating neuronal cell death.