The Appendix and Parkinson's - Are we Better Off Without One? Researchers at the Van Andel Institute in Michigan have published a research report - which was partly supported by The Cure Parkinson's Trust - in the prestigious journal, Science Translational Medicine. The study reports that the human appendix contains high levels of misfolded alpha-synuclein protein and that removal of the appendix decreased one’s risk of developing Parkinson’s. Alpha synuclein is a protein that is intimately associated with Parkinson's, in that it clusters (or aggregates) together in the brains of people with Parkinson's. These aggregates contained 'misfolded' versions of the protein which are believed to be passed from cell to cell, resulting in the slow progressive nature of the condition. Accumulation of aggregated alpha-synuclein has been suggested begins in the gastrointestinal tract. In two independent dataset studies looking at the incidence and distribution of PD, involving more than 1.6 million individuals, the researchers observed that removal of the appendix decades before disease onset was associated with a lower risk for PD, and delayed the age of PD onset. This research is the latest to implicate the gut and the immune system in the development of the disease. Parkinson’s (PD) is clinically diagnosed on the basis of motor symptoms that result from the progressive loss of dopaminergic neurons in the midbrain. However, it is now recognised that PD is a multisystem disorder involving both motor and non-motor features, involving both the central and peripheral nervous system. Gastrointestinal (GI) dysfunction is a common non-motor symptom of PD, often preceding the onset of motor symptoms sometimes by decades. PD pathology, consisting of aggregated alpha-synuclein, has been detected in GI neurons in patients with PD, and alpha-synuclein aggregates in the GI can occur early on before motor symptoms appear in what is termed the 'prodromal phase'. Because of the early appearance of alpha-synuclein aggregates in the GI tract of patients with PD and their capacity to ascend the vagal nerve to the brain, it has been suggested that the GI tract could be the origin of PD. Accumulation of alpha-synuclein in the GI tract occurs in response to toxins and bacteria which activate the immune system. This may signify that GI tract regions with regular interactions with environmental pathogens and enhanced immunosurveillance have a greater risk of developing the alpha-synuclein abnormalities seen in PD. Although the appendix is often considered to be an organ of little importance, it is rich in immune cells, and a primary function of the appendix is to assist the immune system in the detection and removal of pathogens, as well as to regulate intestinal microbiome. Consequently, the appendix may be prone to accumulating alpha-synuclein pathology that affects PD risk, although this has yet to be investigated in detail. Given the recent research linking gut inflammation to PD and the role of the appendix in immune response and microbiome regulation, it is possible that the appendix contributes to PD via inflammation and microbiome alterations. Given that the appendix is responsible for monitoring and repopulating the microbiome in the small and large intestine, any inflammation in the appendix may signify the presence of pro-inflammatory bacteria, which would then be dispersed throughout the intestine. If the appendix were to house bacteria that promote inflammation in the brain, this may also increase the risk of developing PD. In summary, this study shows that the appendix is a rich, lifelong source of potentially toxic alpha-synuclein, and early removal of the appendix is associated with a reduced risk of developing PD and treatments that limit aberrant alpha-synuclein accumulation in the appendix and other GI tract tissue may be a potential therapeutic strategy for PD.