Environmental Triggers of Parkinson's Disease - Implications of the Braak and Dual-hit Hypotheses

Idiopathic Parkinson's disease (PD) may take decades to develop, during which many risk or protective factors may come into play to initiate the pathogenesis or modify its progression to clinical PD. The lack of understanding of this prodromal phase of PD and the factors involved has been a major hurdle in the study of PD etiology and preventive strategies. Although still controversial, the Braak and dual-hit hypotheses that PD may start peripherally in the olfactory structures and/or the gut provides a theoretical platform to identify the triggers and modifiers of PD prodromal development and progression. This is particularly true for the search of environmental causes of PD as the olfactory structures and gut are the major human mucosal interfaces with the environment. In this review, we lay out our personal views about how the Braak and dual-hit hypotheses may help us search for the environmental triggers and modifiers for PD, summarize available experimental and epidemiological evidence, and discuss research gaps and strategies.