Implications for Parkinson ' s Disease

Parkinson's disease occurs in approximately one percent of individuals over the age of 55. It is characterized by the presence oftremor, rigidity, and bradykinesia. Pathologically, the hallmark of Parkinson's disease is the progressive degeneration of the dopamine (DA)-containing neurons of the nigrostriatal projection. Neurological deficits associated with the loss of DA neurons do not appear until the degeneration is extensive, presumably due to compensatory properties of the remaining DA neurons and their targets (Bernheimer et ai., 1973; Zigmond et aI., 1984). The mechanism responsible for the degenerative process is not known, although factors such as genetic predisposition and environmental toxins have been proposed to playa role (Agid et aI., 1993). There is also growing evidence that endogenous factors such as oxidative stress and DA itself may contribute to the neurodegenerative process (Cohen, 1983; Agid et aI., 1993; Zigmond et ai., 1992). A role for DA-induced toxicity to DA neurons is supported by several lines of evidence. First, like the neurotoxin 6-hydroxydopamine, DA is an unstable molecule that will oxidize to form reactive oxygen species and quinones (Graham, 1978). Second, the accumulation of the dark pigment neuromelanin in DA-containing cells of the substantia nigra is positively correlated with the susceptibility of these neurons to degradation in Parkinson's disease (Hirsch et ai., 1988; Kastner et aI., 1992). Neuromelanin is the polymerization product of oxidized DA, suggesting that oxidation is occurring within DA-containing neurons. Likewise, free cysteinyl-DA, the cysteine conjugated form of oxidized DA, has been found in DA-rich regions of the brain in a variety of species and used as an index of the rate of DA autoxidation (Fornstedt et aI., 1990a). Levels of free cysteinyl-catechols are increased under conditions known to promote oxidative stress, such as aging (Fornstedt et ai., 1990b) or ascorbate deficiency (Fornstedt and Carlsson, 1991). Third, the exposure of cells to DA, either in vivo or in vitro, has neurotoxic consequences (Graham et aI., 1978; Michel and Hefti, 1990; Filloux and Townsend, 1993). Finally, pharmacological depletion