Cerebral calpain in fatal falciparum malaria.
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.
Medana
I M
IM
Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK. isabelle.medana@ndcls.ox.ac.uk
Day
N P
NP
Hien
T T
TT
Mai
N T H
NT
Bethell
D
D
Phu
N H
NH
Turner
G D
GD
Farrar
J
J
White
N J
NJ
Esiri
M M
MM
D015526:AIDS Dementia Complex / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D001370:Axonal Transport; D001369:Axons / Q000201:enzymology / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology; D004912:Erythrocytes / Q000469:parasitology / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007968:Leukoencephalopathy, Progressive Multifocal / Q000378:metabolism / Q000473:pathology; D016778:Malaria, Falciparum / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009457:Neuroglia / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure
D002135:Calcium-Binding Proteins; C033668:calpastatin; D002154:Calpain; C449000:m-calpain; C449002:mu-calpain