NIGROSTRIATAL NEURONAL DEATH IN PARKINSONS-DISEASE - A PASSIVE OR AN ACTIVE GENETICALLY-CONTROLLED PROCESS

The cause for the rather selective degeneration of the nigrostriatal d opaminergic (DA) neurons in Parkinson's disease (PD) is still enigmati c. The major current hypothesis suggests that nigral neuronal death in PD is due to excessive oxidant stress generated by auto- and enzymati c oxidation of DA, formation of neuromelanin and presence of high conc entrations of iron. Such cell death is generally regarded as a passive , necrotic process, mainly resulting from membrane lipid peroxidation, leading to its dysfunction and rupture and then to neuronal disintegr ation. We suggest a novel approach, that views neuronal degeneration i n PD as an active process that occurs mainly the nuclear level. Our co ncept is based on the following observations: (1) Nigral histopatholog y in PD is characterized by a slow, protracted degeneration of individ ual neurons. We propose that it may be due to apoptosis [programmed ce ll-death (PCD), an active, genetically-controlled, intrinsic program o f cell ''suicide''] rather than to necrotic cell death. (2) DA exerts antitumor effect on melanoma and neuroblastoma cells. (3) Many antican cer drugs, trigger PCD by causing DNA damage. (4) DA has been shown to be genotoxic. (5) We recently first showed that DA, the endogenous ne urotransmitter in the nigra, can trigger apoptosis in cultured, postmi totic sympathetic neurons. (6) We have also shown that PC-12 cells, tr ansfected with the bcl-2 gene (a proto-oncogene that inhibits PCD) are relatively resistant to DA-apoptotic effect. Degeneration of nigrostr iatal neurons in PD may therefore be linked to dysregulation of the co ntrol mechanisms that normally restrain the PCD-triggering-potential o f their own neurotransmitter.