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Understanding the Development of Compensatory Pathways in a Mutant Malaria Parasite Harbouring Hypomorphic Allele of Plant-Like Kinases
Published on: November 22, 2024
Cerebral calpain in fatal falciparum malaria
I M Medana1, N P Day, T T Hien
1Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK. isabelle.medana@ndcls.ox.ac.uk
Abstract:
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.
Insights
Calpains, enzymes implicated in axonal injury, are linked to neurological damage in cerebral malaria (CM). This study found increased calpain activity in brain tissue from CM patients, suggesting a role in disease progression.
Area of Science:
- Neuroscience
- Pathology
- Biochemistry
Background:
- Axonal transport disruption is a key factor in cerebral malaria (CM) neurological dysfunction.
- Calpains, calcium-activated proteases, are implicated in axonal injury across various neurological diseases.
Purpose of the Study:
- To investigate the association between mu- and m-calpain, calpastatin, and axonal injury in post mortem brain tissue from severe malaria patients.
- To elucidate the role of calpains in the pathogenesis and progression of cerebral malaria.
Main Methods:
- Post mortem brain tissue analysis from severe malaria cases and controls.
- Immunohistochemical labeling for mu-calpain, m-calpain, calpastatin, and beta-amyloid precursor protein (to detect axonal transport impairment).
- Comparison of calpain and calpastatin levels in neurons and glia across different patient groups.
Main Results:
- Calpains were found associated with axons exhibiting impaired axonal transport (beta-amyloid precursor protein positive).
- Elevated calpastatin levels were infrequent in injured axons.
- Increased nuclear mu-calpain was observed in neurons and glia of severe malaria patients compared to controls.
- Calpastatin showed redistribution in Plasmodium falciparum-infected erythrocytes.
Conclusions:
- Calpains are implicated in axonal injury and may play a role in modulating disease progression in cerebral malaria.
- The findings suggest calpain activation is a significant factor in the neurological complications of severe malaria.
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