Etiology and pathogenesis of Parkinson disease.

The etiology of Parkinson disease (PD) is multifactorial and is likely to involve different causes in different patients. Several different genes have been identified as causes of familial PD, including alpha-synuclein gene mutations and multiplications, and mutations of parkin, PINK1, DJ1, and LRRK2. The biochemical consequences of these mutations have served to reinforce the relevance of the pathways to pathogenesis previously characterized, for example, mitochondrial dysfunction, oxidative stress, and protein misfolding and aggregation. The recognition that glucocerebrosidase mutations represent a significant risk factor for PD has focused attention on lysosomal function and autophagy as relevant to PD. Several environmental factors have also been shown to influence the risk for PD, although odds ratios remain relatively modest. Specific toxins can cause dopaminergic cell death in man and animals, but they probably have limited relevance to the etiology of PD.