Synergistic effects of pesticides and metals on the fibrillation of alpha-synuclein: implications for Parkinson's disease.

Aggregation of alpha-synuclein has been implicated in the formation of proteinaceous inclusions in the brain (Lewy bodies, Lewy neurites) that are characteristic of neurodegenerative diseases, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLBs). The etiology of PD is unknown, but recent work has shown that except in rare cases, there appears to be no direct genetic basis. However, several studies have implicated environmental factors, especially pesticides and metals. Here we show that certain pesticides and metals induce a conformational change in alpha-synuclein and directly accelerate the rate of formation of alpha-synuclein fibrils in vitro. In addition, the simultaneous presence of metal and pesticide led to synergistic effects on the rate of fibrillation. We propose a model in which environmentalfactors in conjunction with genetic susceptibility may form the underlying molecular basis for idiopathic PD.