GLUTATHIONE IS INVOLVED IN THE GRANULAR STORAGE OF DOPAMINE IN RAT PC12 PHEOCHROMOCYTOMA CELLS - IMPLICATIONS FOR THE PATHOGENESIS OF PARKINSONS-DISEASE

Parkinson's disease (PD) is characterized by degeneration of dopamine (DA)-containing nigro-striatal neurons. Loss of the antioxidant glutat hione (GSH) has been implicated in the pathogenesis of PD. Previously, we showed that the oxidant hydrogen peroxide inhibits vesicular uptak e of DA in nigro-striatal neurons. Hydrogen peroxide is scavenged by G SH and, therefore, we investigated a possible link between the process of vesicular storage of DA and GSH metabolism. For this purpose, we u sed rat pheochromocytoma-derived PC12 cells, a model system applied ex tensively for studying monoamine storage mechanisms. We show that depl etion of endogenous DA stores with reserpine was accompanied in PC12 c ells by a long lasting, significant increase in GSH content the extent of which appeared to be inversely related to the rate of GSH synthesi s. A similar increase in GSH content was observed after depletion of D A stores with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosi ne. in the presence of alpha-methyl-p-tyrosine, refilling of the DA st ores by exogenous DA reduced GSH content back to control level. Loweri ng of PC12 GSH content, via blockade of its synthesis with buthionine sulfoximine, however, led to a significantly decreased accumulation of exogenous [H-3]DA without affecting uptake of the acetylcholine precu rsor [C-14]choline. These data suggest that GSH is involved in the gra nular storage of DA in PC12 cells and that, considering the molecular characteristics of the granular transport system, it is likely that GS H is used to protect susceptible parts of this system against (possibl y DA-induced) oxidative damage.