Bryan A. Killinger, Zachary Madaj, Jacek W. Sikora, Nolwen Rey,
Alec J. Haas, Yamini Vepa, Daniel Lindqvist, Honglei Chen, Paul M. Thomas, Patrik Brundin, Lena Brundin, Viviane Labrie
The pathogenesis of Parkinson’s disease (PD) involves the accumulation of aggregated alpha-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 alpha-synuclein aggregates and an abundance of PD pathology–associated alpha-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 alpha-synuclein. Together, we propose that the normal human appendix con- tains pathogenic forms of alpha-synuclein that affect the risk of developing PD.