Is Bax a mitochondrial mediator in apoptotic death of dopaminergic neuronsin Parkinson's disease?

Bax is a proapoptotic member of the Bcl-2 family of proteins. It is believe d to exert its action primarily by facilitating the release of cytochrome c from the mitochondrial intermembrane space into the cytosol, leading to ca spase activation and cell death. Because alterations in mitochondrial respi ratory function, caspase activation and cell death with morphologic feature s compatible with apoptosis have been observed post mortem in the brain of patients with Parkinson's disease, we tried to clarify the potential role o f Bax in this process in an immunohistochemical study on normal and Parkins on's disease post-mortem brain and primary mesencephalic cell cultures trea ted with MPP+. We found that Bax is expressed ubiquitously by dopaminergic (DA) neurons in postmortem brain of normal and Parkinson's disease subjects as well as in vitro. Using an antibody to Bax inserted into the outer mito chondrial membrane as an index of Bax activation, no significant difference s were observed between control and Parkinson's disease subjects, regardles s of the mesencephalic subregion analysed. However, in Parkinson's disease subjects, the percentage of Bax-positive melanized SNpc neurons containing Lewy bodies, suggestive of DA neuronal suffering, was significantly higher than the overall percentage of Bax-positive neurons among melanized neurons . Furthermore, all melanized SNpc neurons in Parkinson's disease subjects w ith activated caspase-3 were also immunoreactive for Bax, suggesting that B ax anchored in the outer mitochondrial membrane of melanized SNpc neurons s howing signs of neuronal suffering or apoptosis is increased compared with DA neurons that are apparently unaltered. Surprisingly, MPP+ treatment of t yrosine hydroxylase (TH)-positive neurons in primary mesencephalic cultures did not cause redistribution of Bax, although cytochrome c was released fr om the mitochondria and nuclear condensation/fragmentation was induced. Tak en together, these findings suggest that in the human pathology, Bax may be a cofactor in caspase activation, but our in vitro data fail to indicate a central role for Bax in apoptotic death of DA neurons in an experimental P arkinson's disease paradigm.