Etiology and pathogenesis of Parkinson's disease.

The past 25 years have seen a major expansion of knowledge concerning the cause of Parkinson's disease provided by an understanding of environmental and genetic factors that underlie the loss of nigral dopaminergic neurons. Based on the actions of toxins, postmortem investigations, and gene defects responsible for familial Parkinson's disease, there is now a general consensus about the mechanisms of cell death that contribute to neuronal loss in Parkinson's disease. Mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammatory change are considered to lead to cell dysfunction and death by apoptosis or autophagy. Ageing is the single most important risk factor for Parkinson's disease, and the biochemical changes that are a consequence of aging amplify these abnormalities in Parkinson's disease brain. What remains to be determined is the combination and sequence of events leading to cell death and whether this is identical in all brain regions where pathology occurs and in all individuals with Parkinson's disease. Focusing on those events that characterize Parkinson's disease, namely, mitochondrial dysfunction and Lewy body formation, may be the key to further advancing the understanding of pathogenesis and to taking these mechanisms forward as a means of defining targets for neuroprotection.