| The etiologic basis of Parkinson's disease (PD), the second most common age-related neurodegenerative disorder, is unknown. Recent epidemiological and experimental studies indicate that exposure to environmental toxins, including MPTP, paraquat and maneb, may contribute to the pathogenesis of PD. These toxins, when administrated systemically, can cause selective degeneration of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc), which reproduce specific feature of PD. Determining the cell death mechanisms involved is important to understand the environmental component of idiopathic PD. Using human SK-N-SH cells, we have found that paraquat, maneb and MPP+ (the active metabolite of MPTP) induced apoptotic cell death that included the classic morphological changes, caspase-3 activation and cytochrome c release. As cytochrome c release is regulated by members of Bcl-2 family, we compared the effects of paraquat, maneb and MPP + on all members of the Bcl-2 family. Although all of these toxins are known to stimulate the production of reactive oxygen species (ROS), we have found that these chemicals alter different expression of Bcl-2 family members. Paraquat induced Bak, BNip3 and Noxa levels, whereas MPP+ neurotoxicity involved Bax. Maneb increased both Bax and Bak, as well as Noxa and BNip3. Small interfering RNA (SiRNA) studies have been used to confirm the physiological importance of these changes in our system. Further, in vivo, we have found that Paraquat injected mice showed stronger BNip3 and Bak immunoreactivity in the Substantica Nigra and Bak-deficient mice were resistant to PQ-induced depletion of TH+ neurons in the SNpc. These findings suggest that although these toxins impact ROS, they have divergent effects on subsequent signal transduction. However, paraquat, maneb and MPP+ induce apoptosis by mechanisms that ultimately converge on at the mitochondria. |
