UNDERSTANDING CELL-DEATH IN PARKINSONS-DISEASE

Current concepts of the cause of Parkinson's disease (PD) suggest a ro le for both genetic and environmental influences. Common to a variety of potential causes of nigral cell degeneration in PD is the involveme nt of oxidative stress. Postmortem analysis shows increased levels of iron, decreased complex I activity, and a decrease in reduced glutathi one (GSH) levels. The decrease in GSH levels may be a particularly imp ortant component of the cascade of events leading to cell death becaus e it occurs in the presymptomatic stage of PD and may directly induce nigral cell degeneration or render neurons susceptible to the actions of toxins. There is evidence suggesting that oxidative stress might or iginate in glial cells rather than in neurons, and alterations in glia l function may be an important contributor to the pathologic process t hat occurs in PD. Oxidative damage occurs in the brain in PD, as shown by increased lipid peroxidation and DNA damage in the substantia nigr a. Increased protein oxidation is also apparent, but this occurs in ma ny areas of the brain and raises the specter of a more widespread path ologic process occurring in PD to which the substantia nigra is partic ularly vulnerable. The inability of the substantia nigra to handle dam aged or mutant (eg, alpha-synuclein) proteins may lead to their aggreg ation and deposition and to the formation of Lewy bodies. Indeed, Lewy bodies stain for both alpha-synuclein and nitrated proteins. Current evidence enables us to hypothesize that a failure to process structura lly modified proteins in regions of the brain exhibiting oxidative str ess is a cause of both familial and sporadic PD.