A squishy, 4-inch gut organ whose function has baffled anatomists for centuries is about to have its moment of fame: The lowly appendix, scientists reported in a study on Wednesday, can initiate Parkinson’s disease.

It does so, they suspect, by serving as a reservoir of misfolded, clumping, neurotoxic proteins that travel to the brainstem via the vagus nerve, which runs from the gut all the way up to the brain. People who had their appendix removed have an almost 20 percent lower risk of Parkinson’s, according to the study in Science Translational Medicine, or a risk of 1.6 per 10,000 people over a decade compared to 1.98 in the general population.

The discovery that appendectomy might reduce but doesn’t eliminate the risk of Parkinson’s shows there are other causes of the disease, a usually-crippling brain disorder that strikes about 60,000 people in the U.S. every year. In addition, appendectomy reduced the risk only in people living in rural areas, not urban ones; not among those who inherited any of three common Parkinson’s-causing mutations, which account for about 10 percent of cases; and only if the surgery occurred early in life, well before Parkinson’s started.

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Rather than weakening the study, however, those qualifications might actually support its explanation of how the appendix (which is attached to the large intestine) can trigger Parkinson’s. That explanation is based on appendectomy data as well as molecular evidence, in particular that the appendixes of Parkinson’s patients contain clumps of a protein called alpha-synuclein very similar to those in Parkinson’s-affected brains.

“It’s a really nice study, and all of their ideas are biologically plausible,” said James Beck, chief scientific officer of the Parkinson’s Foundation, which was not involved in the research. “It connects the epidemiology, about appendectomy reducing the risk of Parkinson’s, with the basic science.”

Although the appendix is often described as useless or vestigial, it plays a role in the immune system, including by affecting the composition of the gut microbiome and detecting and removing pathogens.

The findings do not mean that everyone worried about Parkinson’s should have an appendectomy, cautioned the study’s senior author, Viviane Labrie of the Van Andel Research Institute in Grand Rapids, Mich. Nor does it mean that everyone with an appendix is likely to develop the disease. It is “a” site of origin for the disease, she said, “but it likely has many sites of origin, including the brain.”

The research does, however, suggest new, appendix-centered approaches to preventing or treating Parkinson’s, which destroys dopamine-making cells in the brain’s substantia nigra. Today’s drugs can replace the lost dopamine but not the destroyed neurons, so although they partly (and temporarily) alleviate symptoms such as tremor and stiffness, they do nothing to stop disease progression.

The new study marshals two lines of evidence for an appendix-Parkinson’s connection, which started off as what Beck calls “a weird idea” in 2003.

The first evidence comes from large databases. One, with medical and demographic information on 1.6 million Swedes going back to 1964, showed that people who’d had an appendectomy were 19.3 percent less likely to develop Parkinson’s. When the scientists analyzed urban and rural residents separately, however, they found no such protective effect in the former. Another data set, of 849 Parkinson’s patients, showed that in those who had an appendectomy, the disease appeared an average of 3.6 years later than in patients who still had their appendix — but again, only for rural residents.

The second line of evidence comes from scrutiny of dozens of appendixes. Parkinson’s patients’ had clumps of alpha-synuclein virtually identical to those in Parkinson’s brains. So did healthy people, but Parkinson’s patients had 4.5 times as much of the short form of alpha-synuclein, which is more prone to clumping into the neurotoxic aggregates than the long form.

“The appendix is a hub for the accumulation of clumped forms of alpha-synuclein proteins,” the exact same aggregates found in Parkinson’s brains, said Bryan Killinger, the study’s first author and a postdoctoral fellow in Labrie’s lab.

Clumps of alpha-synuclein don’t seem to harm the appendix. But “the protein doesn’t like to stay put,” said Labrie. “It travels from neuron to neuron, including into the vagus nerve” from the appendix up to the brainstem. As it happens, where the vagus enters the brainstem is one of the first brain regions to contain alpha-synuclein. And it’s probably no coincidence that cutting the vagus, as was once done to cure ulcers (it didn’t), reduced the risk of Parkinson’s, according to previous studies. “That was an aha moment,” Beck said. “It added weight to the gut-brain hypothesis of Parkinson’s.”

The presence of pathogenic forms of alpha-synuclein in the appendixes of people both with and without Parkinson’s shows that a “second hit” — which Labrie has started to look for — is necessary for the disease to develop: More than 99 percent of people manage to avoid Parkinson’s, appendix or not.

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It’s anyone’s guess what the second hit is. One hint, though, comes from the urban-rural divide in the protective effect of appendectomy, as well as the finding that it’s protective only in people with a non-genetic family history of the disease. A non-genetic cause with a family history suggests shared environments, not shared DNA.

Those facts suggest that alpha-synuclein in the appendix becomes more abundant, more pathogenic, or more upwardly mobile in the presence of something found in the countryside more than cities. Pesticides, well water, and farming, for instance, have been linked to a higher risk of Parkinson’s since 1998.

For new drug possibilities, the Van Andel team suggests compounds that cut alpha-synuclein in the gut. Alpha-synuclein-targeted drugs to treat Parkinson’s have been in development for years, but almost always with the idea of delivering them to the brain. It would almost certainly be easier and safer to target the gut.

As it happens, compounds called metalloproteases, which have been tested against cancer (unsuccessfully), might be repurposed to inhibit enzymes that cut alpha-synuclein into the short, clumping, disease-causing form. It might “be an effective strategy for the treatment or even prevention” of Parkinson’s, the scientists wrote.

A more karmic argument for the appendix-Parkinson’s link: Dr. James Parkinson (1755 to 1824), for whom the disease is named, was the first English physician to describe a case of appendicitis.

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  • It might be significant for a-syncuclein to act as an antimicrobial/antifungal that 2 naturally occurring antifungal peptides, Cecropin (35 aa) and Dermaseptin (29 aa), each have significant homology to the initial portion of a-synuclein. Cecropin has 25 identical or similar amino acids to the early portion of a-synuclein, while dermaseptin has 24 identical or similar amino acids to the same portion of a-synuclein.

    See Uniprot Align with pairing of P37840 with either P14666 or P84936 for verification.

  • I’d love to see someone with the database access look at the statistical correlation between the regional crops in Sweden and the instances of PD that developed. If it is a specific fungi or organism, finding a tie between those that are specific growing to particular host plant should be relatively easy. Wiki: Wheat, barley, sugar beets, oilseeds, potatoes, and staple vegetables dominate in the south, while in the north hay and potatoes are the main crops.

  • Parkinson’s like symptoms in cows from eating corn with fungi:

    A tremorgenic mycotoxicosis of cattle caused by maize sprouts infested with Aspergillus clavatu

    Onderstepoort J Vet Res. 1984 Dec;51(4):271-4.

    An outbreak of disease affecting a herd of 16 dairy cattle which were fed mouldy, sprouted maize is described. Eight of the cattle were affected, 5 of which died. The clinical signs included muscular tremors, hypersensitivity, ataxia, anorexia and salivation. Aspergillus clavatus was the only fungus isolated from the sprouts. Clinical signs that were indistinguishable from those in the field outbreak were reproduced by dosing the mouldy maize sprouts to a steer and a sheep, and by dosing another sheep with maize inoculated with a pure culture of A. clavatus isolated from the mouldy maize on the farm. Light microscopical examination revealed neuronal degeneration and necrosis in the midbrain, medulla oblongata and spinal cord of all 3 of these animals. The disease is clinically and pathologically indistinguishable from the disease caused by the ingestion of sorghum beer residue, and in certain respects it is similar to toxicoses caused by the ingestion of wheat sprouts and malt sprouts infested with A. clavatus.

    PMID: 6533519

  • Perhaps a-synuclein production follows a time-based route that coincides with migration of a fungi, starting at the appendix and Ending at the Brain, leading to early production at the starting location of the route and late production at the ending destination, so upregulation won’t be synchronous until the later stages of the migration. This chronological phenomenon would also explain the occurrence of PD later in life as a time vs distance phenomenon.

    Also notable that the migration could be facilitated by alternating states of the fungus between active and spore, with only one spore needed to seed the infection into nerve attached to gut, with the spore then activating to fully active organsim, then producing another spore than exits the neuron and crosses the synapse via exosomal movement.
    See:
    Parkinson’s disease; the hibernating spore hypothesis.
    Med Hypotheses. 2017 Jul;104:48-53.

    It’s also notable that aspergillus sp. produces large amounts of L-dopa, potentially explaining tremor symptoms as well as induction of negative feedback loop that could lead to shutdown of L-dopa production by brain cells.

    Production of L-dopa by Aspergillus terreus.
    FEMS Microbiol Lett. 1990 Oct;60(1-2):195-9.

    Biosynthesis of L-DOPA by Aspergillus oryzae.
    Bioresour Technol. 2002 Oct;85(1):25-9.17

    Aspergillus niger PA2: a novel strain for extracellular biotransformation of L-tyrosine into L-DOPA.
    Amino Acids. 2016 May;48(5):1253-62.

  • Perhaps the PD connection to the appendix is with undesirable organisms that reside in the appendix long-term and are never fully eradicated, in accordance with the antimicrobial activity for alpha synuclein observed in this study below. Higher levels of exposure to fungi in rural areas vs urban is consistent with this explanation.

    Functional characterization of alpha-synuclein protein with antimicrobial activity.
    Biochem Biophys Res Commun. 2016 Sep 16;478(2):924-8.
    “Here we demonstrate that α-Syn exhibits antibacterial activity against Escherichia coli and Staphylococcus aureus. In addition, we demonstrate a role for α-Syn in inhibiting various pathogenic fungal strains such as Aspergillus flavus, Aspergillus fumigatus and Rhizoctonia solani. We also analyzed localizations of recombinant α-Syn protein in E. coli and Candida albicans. These results suggest that in addition to α-Syn’s role in neurotransmitter release, it appears to be a natural AMP.”
    PMID: 27520375

  • If the appendectomy doesn’t change the urban onset of Parkinson’s why would the country environment be considered a cause? “In addition, appendectomy reduced the risk only in people living in rural areas, not urban ones;…” “Those facts suggest that alpha-synuclein in the appendix becomes more abundant, more pathogenic, or more upwardly mobile in the presence of something found in the countryside more than cities.” Perhaps the country environment helps prevent Parkinson’s or an urban environment doesn’t? Something seems to have been mixed up in the article. I re-read it several times to see if I missed something.

    • More frequent exposure to fungi in rural areas could account for the difference, as explained in the two comments above. This is especially significant for fungi that grow on farm crops, that may also be found in vegetable gardens.

  • Wonder how early in life the appendectomy must be done to be protective — teen years?? college age??
    Some varieties of Parkinson’s seem to develop in the early 50s…

  • Rural? Tick bites carrying Mycoplasma, a great facilitator for viruses. Wouldn’t be surprised if same with Alzheimer’s.

  • Isn’t still possible that the relationship is still associative? Possibly something to do with the immune system in people who suffered an acute appendicitis?

  • Proposing prophylactic drug regimens to cut the risk of Parkinson from 0.02% to 0.016% is simply ridiculous. Although, I am sure some pharma companies will try to sell it as the next big thing

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