Understanding cell death in Parkinson's disease.

Current concepts of the cause of Parkinson's disease (PD) suggest a role for both genetic and environmental influences. Common to a variety of potential causes of nigral cell degeneration in PD is the involvement of oxidative stress. Postmortem analysis shows increased levels of iron, decreased complex I activity, and a decrease in reduced glutathione (GSH) levels. The decrease in GSH levels may be a particularly important component of the cascade of events leading to cell death because 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 originate in glial cells rather than in neurons, and alterations in glial function may be an important contributor to the pathologic process that occurs in PD. Oxidative damage occurs in the brain in PD, as shown by increased lipid peroxidation and DNA damage in the substantia nigra. Increased protein oxidation is also apparent, but this occurs in many areas of the brain and raises the specter of a more widespread pathologic process occurring in PD to which the substantia nigra is particularly vulnerable. The inability of the substantia nigra to handle damaged or mutant (eg, alpha-synuclein) proteins may lead to their aggregation 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 structurally modified proteins in regions of the brain exhibiting oxidative stress is a cause of both familial and sporadic PD.