LAUSR

The human appendix is a reservoir for α-synuclein aggregates and its removal may reduce the risk of Parkinson’s disease. The benefits of a missing appendix Misfolded α-synuclein is a pathological hallmark of Parkinson’s disease (PD). Killinger et al. now report that the human appendix contains an abundance of misfolded α-synuclein and that removal of the appendix decreased the risk of developing PD. The appendix of both PD cases and healthy individuals contained abnormally cleaved and aggregated forms of α-synuclein, analogous to those found in postmortem brain tissue from patients with PD. Furthermore, α-synuclein derived from the appendix seeded rapid aggregation of recombinant α-synuclein in vitro. In two large-scale epidemiological studies, the authors demonstrated that an appendectomy occurring decades prior reduced the risk of developing PD, suggesting that the appendix may be implicated in PD initiation. The pathogenesis of Parkinson’s disease (PD) involves the accumulation of aggregated α-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 α-synuclein aggregates and an abundance of PD pathology–associated α-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 α-synuclein. Together, we propose that the normal human appendix contains pathogenic forms of α-synuclein that affect the risk of developing PD.