Etiology of Parkinson's disease.

The etiology of Parkinson's disease (PD) has long been thought to involve both genetic and environmental factors, but until recently there has been no direct evidence to support either one as a causative factor. However, in the past 8 years six different genes have been identified as causing familial PD. Together, they support the notion that common pathogenetic mechanisms exist across the etiologic spectrum of PD. Specifically, mutations in alpha-synuclein, parkin, UCHL1, DJ1, PINK1, and LRRK2 cause PD, with a Mendelian pattern of inheritance. DJ1 and PINK1 are mitochondrial proteins and overexpression of alpha-synuclein and parkin induce mitochondrial defects. These same proteins are involved in the response to oxidative stress and affect proteasomal function. In contrast, few environmental factors have been characterized. Nevertheless, those toxins that have been demonstrated to have the ability to cause nigrostriatal cell death appear to interact by interfering with mitochondrial function, inducing oxidative stress, and modifying proteasomal function. Therefore, common themes are beginning to emerge in the etiopathogenesis of PD. This bodes well for research focused on the development of treatments that will modify the course of PD.