The calcium-activated neutral proteases (CANP, calpains) have been implicated in both acute and chronic neurodegenerative processes. In the present study, we analyzed the in situ mRNA expression of calpain I and II and their endogenous inhibitor, calpastatin, in the motor neuron degeneration (Mnd) mutant mouse, which exhibits progressive dysfunction of the spinal cord and brain. As the disease progresses, the mutants show increasingly pronounced motor abnormalities which coincide with swelling of the spinal motor neurons, neocortex, hippocampal CA regions and cerebellar Purkinje cells. In situ hybridization studies show that the Mnd mice have a significantly higher level of calpain I, calpain II and calpastatin than the congenic controls in the following brain regions and cell types: hippocampal CA3 region, pyramidal cells, cerebellar Purkinje cells and spinal cord motor neurons. However, no differences in calpain or calpastatin mRNA levels are observed in glial and cerebellar granule cells of Mnd and control mice. Western blots and competitive RT-PCR analyses of brain and spinal cord homogenates are confirmative. Such altered gene expression in specific cell types of brain and spinal cord suggests the involvement of the calpain/calpastatin system.