Cerebral calpain in fatal falciparum malaria.
Medana IM., Day NP., Hien TT., Mai NT., Bethell D., Phu NH., Turner GD., Farrar J., White NJ., Esiri MM.
Disruption of axonal transport may represent a final common pathway leading to neurological dysfunction in cerebral malaria (CM). Calpains are calcium (Ca2+)-activated cysteine proteases which have been implicated in axonal injury in neurological diseases of various aetiologies. In this study we examined the association between mu- and m-calpain, the specific inhibitor calpastatin, and axonal injury in post mortem brain tissue from patients who died from severe malaria. Calpains were associated with axons labelled for the beta-amyloid precursor protein that detects impaired axonal transport. Elevated levels of calpastatin were rarely observed in injured axons. There were increased numbers of neurones with mu-calpain in the nuclear compartment in severe malaria cases compared with non-neurological controls, and increased numbers of glia with nuclear mu-calpain in CM patients compared with non-CM malaria cases and non-neurological controls. There was marked redistribution of calpastatin in the sequestered Plasmodium falciparum-infected erythrocytes. Responses specific to malaria infection were ascertained following analysis of brain samples from fatal cases with acute axonal injury, HIV encephalitis, and progressive multifocal leucoencephalopathy. Our findings implicate a role for calpains in the modulation of disease progression in CM.