Parkinson's disease is characterized by a selective loss of dopaminergic neurons in the nigrostriatal pathway. However, not all dopaminergic neurons degenerate in this disease, and
calcium has been suspected of playing a role in this differential vulnerability. An overexpression of the
calcium-dependent
protease calpain II has recently been reported in the parkinsonian substantia nigra, suggesting that a rise in intracellular
calcium concentrations may be involved in the mechanism leading to cell death. The proteasic activity of
calpain is regulated by an endogenous inhibitory
protein called
calpastatin. Because little is known about the distribution of
calpastatin in the primate brain, we first analyzed immunohistochemically the
calpastatin 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 the thalamus. The cerebellum was stained intensely, particularly in the granular and Purkinje cell layers. A dense, heterogeneous staining was observed in the hippocampal formation, mostly in the pyramidal and granular layers. The distribution of staining was similar in the different cerebral cortices studied, and it was most intense in layer V. In the brainstem, staining was particularly prominent in the substantia nigra pars reticulata and compacta, the central gray substance, the superior colliculus, and the cuneiform nucleus, and staining was moderate in the tegmenti pedonculopontinus nucleus 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 revealed that some dopaminergic neurons coexpress
calpastatin, the proportion of double-stained neurons ranging between 52% and 76% among the different dopaminergic cell groups. Quantitative analysis of the number of
calpastatin-stained neurons evidenced a loss of both
calpastatin-positive and
calpastatin-negative neurons in the substantia nigra of patients with
Parkinson's disease. These data suggest that
calpain II overexpression in
Parkinson's disease is not compensated for by a concomitant increase in
calpastatin expression.