Calpastatin immunoreactivity in the monkey and human brain of control subjects and patients with Parkinson's disease

Parkinson's disease is characterized by a selective loss of dopaminergic ne urons in the nigrostriatal pathway. However, not all dopaminergic neurons d egenerate in this disease, and calcium has been suspected of playing a role in this differential vulnerability. An overexpression of the calcium-depen dent protease calpain II has recently been reported in the parkinsonian sub stantia nigra, suggesting that a rise in intracellular calcium concentratio ns may be involved in the mechanism leading to cell death. The proteasic ac tivity of calpain is regulated by an endogenous inhibitory protein called c alpastatin. Because little is known about the distribution of calpastatin i n the primate brain, we first analyzed immunohistochemically the calpastati n expression in normal human and monkey brain. A ubiquitous distribution of calpastatin immunostaining was observed in both cases, but its expression was variable from one region to another. In the basal ganglia, staining was intense in the striatum, in the pallidal complex, and in some nuclei of th e thalamus. The cerebellum was stained intensely, particularly in the gran granular and Purkinje cell layers. A dense, heterogeneous staining was obse rved in the hippocampal formation, mostly in the pyramidal and granular lay ers. The distribution of staining was similar in the different cerebral cor tices studied, and it was most intense in layer V. In the brainstem, staini ng was particularly prominent in the substantia nigra pars reticulata and c ompacta, the central gray substance, the superior colliculus, and the cunei form nucleus, and staining was moderate in the tegmenti pedonculopontinus n ucleus and the griseum pontis. In the second part of the study, the authors compared calpastatin expression in the mesencephalon between patients with Parkinson's disease and control subjects. Sequential double staining revea led that some dopaminergic neurons coexpress calpastatin, the proportion of double-stained neurons ranging between 52% and 76% among the different dop aminergic cell groups. Quantitative analysis of the number of calpastatin-s tained neurons evidenced a loss of both calpastatin-positive and calpastati n-negative neurons in the substantia nigra of patients with Parkinson's dis ease. These data suggest that calpain II overexpression in Parkinson's dise ase is not compensated for by a concomitant increase in calpastatin express ion. (C) 2000 Wiley-Liss, Inc.