Gene-environment interactions in Parkinson's disease: the importance of animal modeling

Parkinson's disease (PD), a late-onset neurodegenerative disorder, occurs most commonly in a "sporadic" (idiopathic) form, without a clearly defined genetic basis and only a vaguely delineated pathogenesis. Together, the various monogenic forms of PD (i.e., those arising from mutations in single genes) account for a minority of PD cases but have provided crucial insights into disease mechanisms. Although it is commonly believed that sporadic PD is caused by a lifetime of environmental exposures that are superimposed on an individual's composite genetic susceptibility, this hypothesis has not been tested adequately. This article reviews genetic and environmental factors that have been associated with PD and attempts to put these into a pathogenic framework. We argue that animal modeling will become increasingly important in attempting to elucidate gene-environment interactions, to define pathogenic mechanisms, and to provide a platform for testing of targeted therapeutic interventions.