Proteolytic breakdown of cytoskeleton induces neurodegeneration during pathology of murine cerebral malaria

Fatal murine cerebral malaria is known to induce cellular degeneration by altering cellular morphology and integrity of cell. The morphology and integrity of the cell mainly depends on the cytoskeletal network of the cell. Increased proteolysis of cytoskeletal proteins accompanied by aggravated suicidal proteases activation leads to cellular degeneration. In the present study, we investigated the roles of apoptotic and necrotic cell death proteases, caspase-3, calpain-1 and cathepsin-b in the proteolysis of neuronal cytoskeletal proteins in mouse model of fatal cerebral malaria. We found increased levels of calpain-1, cathepsin-b and caspase-3, with extensive cross talks between these suicidal proteases. Increased levels of these proteases correlated with the enhanced proteolysis of several cytoskeletal proteins including neuronal cytoskeleton proteolytic signature fragments. Further, we also observed that increased levels of these proteases correlated with the appearance of neuronal death that exhibited apo-necrotic continuum. Our results confirm that activation of multiple suicidal proteases, their cross talks and breakdown of the cytoskeletal proteins increase neuronal degeneration and lead to exacerbation of cerebral malaria pathology.

► In the present study we report neuronal cell death in the fatal murine cerebral malaria model.
► We find elevated levels of caspase-3, calpain-1 and cathepsin b.
► We find cross talk of these proteases which aggravates the cell death.
► We also found these proteases directly interact with the neuronal cytoskeleton.
► We conclude these proteases directly cleave neuronal cytoskeleton leading to cell death.