Hanna RA, Campbell RL, Davies PL.
Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin.
Nature. 2008 Nov 20;456(7220):409-12.
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The relationship between calpain and its endogenous inhibitor protein calpastatin in Alzheimer disease (AD) has been explored in a study in this week’s Journal of Neuroscience (Rao et al., 2008). The study shows that neuronal calpastatin becomes markedly depleted in AD brain due to abnormally activated caspases 1 and 3 and calpains. Calpastatin depletion is temporally and spatially related to calpain activation in neurons, which in turn is associated with a calpain-related cascade of events leading to neurofibrillary degeneration, including ERK activation, hyperphosphorylation of tau and neurofilaments, and caspase and calpain cleavage of these cytoskeletal proteins. In mice, a similar cascade of molecular events induced by kainate excitotoxicity is substantially ameliorated by maintaining calpastatin at high levels by transgenesis.
The findings strongly suggest that calpastatin depletion represents a tipping point for catastrophic calpain overactivation and downstream events leading to neurodegeneration in AD. They strengthen the case for using mimetics of calpastatin (i.e., highly selective calpain inhibitors) in the therapy of AD. The timely reports by Hanna et al. and Moldoveanu et al. defining the crystal structure of the calcium-dependent protease calpain in complex with calpastatin provide a crucial new tool to overcome the vexing problem of designing inhibitors with high selectivity for calpains.