Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease

Abstract

Caspase-3 is an effector of apoptosis in experimental models of Parkinson's disease (PD). However, its potential role in the human pathology remains to be demonstrated. Using caspase-3 immunohistochemistry on the postmortem human brain, we observed a positive correlation between the degree of neuronal loss in dopaminergic (DA) cell groups affected in the mesencephalon of PD patients and the percentage of caspase-3-positive neurons in these cell groups in control subjects and a significant decrease of caspase-3-positive pigmented neurons in the substantia nigra pars compacta of PD patients compared with controls that also could be observed in an animal model of PD. This suggests that neurons expressing caspase-3 are more sensitive to the pathological process than those that do not express the protein. In addition, using an antibody raised against activated caspase-3, the percentage of active caspase-3-positive neurons among DA neurons was significantly higher in PD patients than in controls. Finally, electron microscopy analysis in the human brain and in vitro data suggest that caspase-3 activation precedes and is not a consequence of apoptotic cell death in PD.T he pathological hallmarks of Parkinson's disease (PD) are a loss of dopaminergic (DA) neurons in the mesencephalon and the presence of Lewy bodies in altered neurons. The exact cause of this neuronal loss is still unknown, but recent human postmortem studies have suggested that, in PD, nigral DA neurons die by apoptosis (1-3) as do DA neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice (4,5), an in vivo model of PD. However, the significance of purely morphological human postmortem features suggestive of apoptosis remained controversial, and the results of investigations into molecular apoptotic markers in PD brains are awaited to confirm the morphologic studies (6).Extensive in vitro studies in nonneuronal and neuronal cell systems indicate that aspartate-specific cysteine proteases (caspases) are effectors of apoptosis (7). In neurons, several lines of evidence indicate that caspase-3 (CPP32͞Yama͞Apopain), a 32-kDa cytosolic protein, plays a major role in the executive phase of apoptosis (8, 9). First, cerebral hyperplasia and cellular disorganization are observed in caspase-3-deficient mice (10). Second, neuronal death in experimental models of several acute and chronic neurodegenerative disorders has been associated with activation of caspase-3 (11-13). Third, with special reference to PD, neurotoxins commonly used to induce experimental parkinsonian syndromes, e.g., 1-methyl-4-phenylpyridinium (MPP ϩ ) and 6-hydroxydopamine (6-OHDA), have been shown to exert their proapoptotic actions via activation of caspase-3-like proteases in neuronal in vitro models (14-16). To date, however, cellular expression of caspase-3 has not been studied in postmortem brain from patients with PD or any other neurologic disorders. In the present study, we thus analyzed caspase-3 distribution and activation in PD and experimental models of the dise...

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