Cerebral dopamine depletion is the hallmark of Parkinson disease. Because dopamine modulates ontogenetic neurogenesis, depletion of dopamine might affect neural precursors in the subependymal zone and subgranular zone of the adult brain. Here we provide ultrastructural evidence showing that highly proliferative precursors in the adult subependymal zone express dopamine receptors and receive dopaminergic afferents. Experimental depletion of dopamine in rodents decreases precursor cell proliferation in both the subependymal zone and the subgranular zone. Proliferation is restored completely by a selective agonist of D2-like (D2L) receptors. Experiments with neural precursors from the adult subependymal zone grown as neurosphere cultures confirm that activation of D2L receptors directly increases the proliferation of these precursors. Consistently, the numbers of proliferating cells in the subependymal zone and neural precursor cells in the subgranular zone and olfactory bulb are reduced in postmortem brains of individuals with Parkinson disease. These observations suggest that the generation of neural precursor cells is impaired in Parkinson disease as a consequence of dopaminergic denervation.

Evidence from postmortem studies suggest an involvement of oxidative stress in the degeneration of dopaminergic neurons in Parkinson disease (PD) that have recently been shown to die by apoptosis, but the relationship between oxidative stress and apoptosis has not yet been elucidated. Activation of the transcription factor NF-B is associated with oxidative stress-induced apoptosis in several nonneuronal in vitro models. To investigate whether it may play a role in PD, we looked for the translocation of NF-B from the cytoplasm to the nucleus, evidence of its activation, in melanized neurons in the mesencephalon of postmortem human brain from five patients with idiopathic PD and seven matched control subjects. In PD patients, the proportion of dopaminergic neurons with immunoreactive NF-B in their nuclei was more than 70-fold that in control subjects. A possible relationship between the nuclear localization of NF-B in mesencephalic neurons of PD patients and oxidative stress in such neurons has been shown in vitro with primary cultures of rat mesencephalon, where translocation of NF-B is preceded by a transient production of free radicals during apoptosis induced by activation of the sphingomyelindependent signaling pathway with C 2

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...