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The pathogenesis of Parkinson's disease (PD) involves the accumulation of aggregated ??-synuclein, which has been suggested to begin in the gastrointestinal tract. Here, we determined the capacity of the appendix to modify PD risk and influence pathogenesis. In two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, we observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset. We also found that the healthy human appendix contained intraneuronal ??-synuclein aggregates and an abundance of PD pathology-associated ??-synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD. Lysates of human appendix tissue induced the rapid cleavage and oligomerization of full-length recombinant ??-synuclein. Together, we propose that the normal human appendix contains pathogenic forms of ??-synuclein that affect the risk of developing PD.

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There have been some potentially significant developments in Parkinson’s disease, which is a good thing to be able to report. As populations age around the world, PD has been on its way up, but therapies for it have not been, despite a good deal of work...