Appendectomy has been associated with a reduced risk of Parkinson’s disease (PD), which supports the potential for a reservoir of aggregated alpha-synuclein in the appendix to affect risk of the condition, according to new epidemiologic and translational evidence from two data sets that promotes a new and emerging theory for PD etiology.
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When placed into the context of other recent studies, these epidemiologic data “point to the appendix as a site of origin for Parkinson’s and provide a path forward for devising new treatment strategies,” reported senior author Viviane Labrie, PhD, of the Van Andel Research Institute (VARI) in Grand Rapids, Mich.
The epidemiologic data was the most recent step in a series of findings summarized in a newly published paper in Science Translational Medicine. As the researchers explained, it is relevant to a separate body of evidence that alpha-synuclein, a protein that serves as the hallmark of PD when it appears in Lewy bodies, can be isolated in the nerve fibers and nerve cells of the appendix.
“We have shown that alpha-synuclein proteins, including the truncated forms observed in Lewy bodies, are abundant in the appendix,” reported first author Bryan A. Killinger, PhD, also at VARI, in a press teleconference. He said this finding is likely to explain the reduced risk of PD from appendectomy.
In the largest of the epidemiologic studies, the effect of appendectomy on subsequent risk of PD was evaluated through the health records from more than 1.6 million individuals in Sweden. The incidence of PD was found to be 19.3% lower among 551,647 patients who had an appendectomy, compared with controls.
In addition, the data showed that when PD did occur after appendectomy, it was delayed on average by 3.6 years. It is notable that appendectomy was not associated with protection from PD in patients with a familial link to PD, a group they said comprises less than 10% of cases.
In patients with PD, nonmotor symptoms often include GI tract dysfunction, which can, in some cases, be part of a prodromal presentation that precedes the onset of classical PD symptoms by several years, the authors reported. However, the new research upends previous conceptions of disease. The demonstration of abundant alpha-synuclein in the appendix coupled with the protective effect of appendectomy, suggests that PD may originate in the GI tract and then spread to the central nervous system (CNS) rather than the other way around.
“The vermiform appendix was once considered to be an unnecessary organ. Although there is now good evidence that the appendix plays a major role in the regulation of the immune system, including the regulation of gut bacteria, our work suggests it is also mediates risk of Parkinson’s,” Dr. Labrie said in the teleconference.
In the paper, numerous pieces of the puzzle are brought together to suggest that alpha-synuclein in the appendix is linked to alpha-synuclein in the CNS. Many of the findings along this investigative pathway were described as surprising. For example, immunohistochemistry studies revealed high amounts of alpha-synuclein in nearly every sample of appendiceal tissue examined, including normal and inflamed tissue, tissue from individuals with PD and those without, and tissues from young and old individuals.
B.A. Killinger et al., Science Translational Medicine (2018)
Staining revealed that healthy appendixes contain alpha-synuclein (red), a protein that is a constituent of the Lewy bodies observed in Parkinson's disease.
“The normal tissue, as well as appendiceal tissue from PD patients, contained high levels of alpha-synuclein in the truncated forms analogous to those seen in Lewy body pathology,” Dr. Killinger said. Based on these and other findings, he believes that alpha-synuclein in the appendix forms a reservoir for seeding the aggregates involved in the pathology of PD, although he acknowledged that it is not yet clear how the proteins in the appendix find their way to the brain.
From these data, it appears that most individuals with an intact appendix have alpha-synuclein in the nerve fibers, but Dr. Labrie pointed out that the only about 1% of the population develops PD. She speculated that there is “some confluence of events,” such as an environmental trigger altering the GI microbiome, that mediates ultimate risk of PD, but she noted that these events may take place decades before signs and symptoms of PD develop. The data appear to be a substantial reorientation in understanding PD.
“We have shown that the appendix is a hub for the accumulation of clumped forms of alpha-synuclein proteins, which are implicated in Parkinson’s,” Dr. Killinger said. “This knowledge will be invaluable as we explore new prevention and treatment strategies.”
The research was funded by a variety of governmental and private grants to individual authors. Dr. Killinger and Dr. Labrie report no financial relationships relevant to this study.
SOURCE: Killinger BA et al. Sci Transl Med. 2018;10:eaar5380.