In the June 27 Journal of Innate Immunity, scientists reported that nerve cells in the gut respond to gastrointestinal viruses by releasing α-synuclein. The researchers, led by Michael Zasloff, Georgetown University School of Medicine, Washington, D.C., used human and mouse white blood cells to determine that the neural protein attracts and activates immune cells. The results imply that α-synuclein plays a part in the gastrointestinal immune system, they wrote, perhaps as a chemoattractant in times of infection. They also claim that chronic inflammation of the intestine might lead to PD, which previously had been linked to accumulation of α-synuclein in the gut. 

Going Viral.

No α-synuclein (brown) appears in a biopsy of a patient’s duodenum (left), however, a month later during infection with a norovirus (right), many neurons (blue) express the protein (right). [Courtesy of Michael Zasloff.]

Some prior evidence hints that α-synuclein might protect against invading microbes. David Beckham, University of Colorado School of Medicine, Denver, reported that α-synuclein protected mice against RNA brain viruses (see Beatman et al., 2015). Others found that rats and worms exposed to certain types of bacteria churned out α-synuclein in both gut and brain as they revved up their immune response (Oct 2016 news). The downside might be pathological accumulation of synuclein aggregates. Researchers led by Kelly Del Tredici and Heiko Braak at the University of Ulm in Germany linked synuclein in the gut to pathological Lewy bodies in PD patients (Braak et al., 2003). In keeping with this idea, researchers at Sarkis Mazmanian’s lab in Caltech in Pasadena have reported that gut bacteria are required for α-synuclein to aggregate and cause motor deficits in mouse models of PD (Dec 2016 news). However, no one had demonstrated that α-synuclein takes part in the normal immune response of the human enteric nervous system, said Zasloff. 

“A lot of data up to now has focused on the central nervous system,” said Beckham, who was not involved in the study. “This is the first paper to show α-synuclein has an immune-related effect in the gastrointestinal nervous system as well.” He found it interesting that α-synuclein might act as a chemoattractant, as its protective mechanism has remained elusive so far.

To test if α-synuclein has a hand in the enteric immune system, first author Ethan Stolzenberg and colleagues focused on children with gut infections. They reasoned this age group has little chance of accumulating α-synuclein associated with preclinical PD. They examined the upper part of the GI tract, which produces little α-synuclein in healthy adults, except in PD. Over nine years, they examined tissue from 42 kids who’d had some sort of gastrointestinal distress—be it duodenitis, gastritis, reactive gastropathy, or infection with Helicobacter pylori, a major cause of intestinal and stomach ulcers. After staining biopsied duodenum, jejunum, and ileum for α-synuclein and markers of neurons and inflammation, the authors found the protein in neuronal processes from every biopsy. The amount of α-synuclein correlated with the degree of inflammation and the number of immune cells in the tissue.

To see if that α-synuclein might occur in the gut before any inflammation there, the authors examined biopsies from an additional 14 children and two adults who had received an intestinal transplant. These patients are monitored closely by endoscopy for signs of tissue rejection. Nine of them just happened to have a norovirus infection within a few months of their last biopsy. Four of them had no α-synuclein in the enteric nerve cells before the infection, while five of them did. In those five the synuclein might have come from a previous illness, Zasloff said. As for the four who were synuclein-free, that changed during the infection. In biopsies taken during the bout with norovirus, α-synuclein had accumulated in nerves of the duodenum (see image above). In addition, biopsies taken one to three months after infection revealed that α-synuclein had stuck around, though at lower levels than during infection. This suggested that cells make α-synuclein in response to microbial attack, the authors said.

The researchers saw that α-synuclein expression in the neuronal processes of the vascular layer of the gut epithelium correlated with an influx of macrophages and dendritic immune cells. The authors wondered if α-synuclein attracted them. Sure enough, both monomeric and synthetic aggregates of the recombinant protein attracted neutrophils and monocytes from the blood of healthy human donors. This fits with data suggesting that α-synuclein attracts microglia in mice (Wang et al., 2015). Moreover, both forms of the protein activated antigen-presenting dendritic cells in vitro. The findings indicate that α-synuclein has an active role in the immune response, rather than simply reflecting neuronal distress.

Given these experiments, the authors proposed that α-synuclein promotes inflammation, rather than resulting from it. This would place it squarely in the middle of defense mechanisms in the human gut, said Zasloff. He suggested that too much α-synuclein—either from a chronic infection, or reduced ability to clear the protein—could cause aggregation and eventually PD. Braak and Del Tredici previously proposed that α-synuclein accumulates in the gut before it climbs up the vagal nerve and spreads to connected brain regions (for a review, see Del Tredici and Braak, 2016). 

“This study fits in nicely with a growing body of literature showing gut infection and microbes may play a role in Parkinson’s,” said Mazmanian. He questioned whether the α-synuclein response was specific, or just one of many proteins upregulated. Still, he said the findings hint at new therapies that target the gut, which might be easier than trying to get drugs across the blood-brain barrier into the central nervous system.—Gwyneth Dickey Zakaib

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  1. The study by Stolzenberg and colleagues represents an important contribution to our understanding of environmental triggers of Parkinson’s pathogenesis. The authors have introduced a novel and welcome twist to the series of studies on gastrointestinal α-synuclein by investigating its expression in young patients, thereby obviating confounding age-related issues. They focus exclusively on the relationship between inflammation/infection and α-synuclein expression. The demonstration of a significant correlation between both acute and chronic inflammation and α-synuclein expression in the gut dovetails nicely with evidence, including that derived from genetic studies, for immune mechanisms in Parkinson’s pathogenesis. More importantly, the possible association with gut infection is interesting in the context of very exciting new research implicating α-synuclein as an antimicrobial peptide. This study also provides a hint regarding the temporal features of this phenomenon. By examining serial biopsies from transplanted patients, they suggest that inflammation-related changes in synuclein expression are indeed dynamic, and perhaps amenable to therapeutic modification. With respect to the transplanted patients however, what the α-synuclein staining represents is not entirely clear. Specifically, are we seeing host-derived synuclein-immunoreactive nerve fibers re-innervating the allograft or degenerating donor-derived fibers?

    Finally, this study may provide an explanation for our observation that the most robust expression of α-synuclein in the gut can be found in the lamina propria of the vermiform appendix. The appendix is an immune organ whose wall is characterized by the presence of abundant lymphoid cells. It would be interesting to know whether increased α-synuclein expression in this organ is a cause or consequence of this. Of more direct relevance to the relationship between acute inflammation and α-synuclein staining shown by Stolzenberg and co-workers, it would be interesting to know whether appendectomy specimens showing appendicitis show elevated expression of α-synuclein. If, as the authors suggest, intestinal inflammation promotes α-synuclein expression and aggregation, is it possible that acute appendicitis represents a precursor to Parkinson’s disease? Unlikely, but this would certainly be an eerie coincidence considering that James Parkinson, with his son John, published one of the first clinical reports of acute appendicitis. 

  2. What an extraordinary insight, Dr. Woulfe! Your beautiful study showing the accumulation of α-synuclein in the appendix of neurologically normal subjects was remarkable (Gray et al., 2013) and we had included its reference in our initial drafts. What I took away from your story was the close apposition of macrophages to the α-synuclein-rich neurites, as well as your observation that those macrophages were chock full of α-synuclein. So it must be that one of the functions of the macrophage that has been attracted to the α-synuclein secreting neurite is garbage disposal work. 

    References:

    . α-synuclein in the appendiceal mucosa of neurologically intact subjects. Mov Disord. 2013 Dec 18; PubMed.

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References

News Citations

  1. Could Bacterial Amyloid Trigger Parkinson’s Pathology?
  2. Do Microbes in the Gut Trigger Parkinson’s Disease?

Paper Citations

  1. . Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain. J Virol. 2015 Dec 30;90(6):2767-82. PubMed.
  2. . Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm. 2003 May;110(5):517-36. PubMed.
  3. . α-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation. Proc Natl Acad Sci U S A. 2015 Apr 14;112(15):E1926-35. Epub 2015 Mar 30 PubMed.
  4. . Review: Sporadic Parkinson's disease: development and distribution of α-synuclein pathology. Neuropathol Appl Neurobiol. 2016 Feb;42(1):33-50. PubMed.

Further Reading

Papers

  1. . The gut microbiome in human neurological disease: A review. Ann Neurol. 2017 Mar;81(3):369-382. Epub 2017 Mar 20 PubMed.
  2. . The gut-brain axis: is intestinal inflammation a silent driver of Parkinson's disease pathogenesis?. NPJ Parkinsons Dis. 2017;3:3. Epub 2017 Jan 11 PubMed.

Primary Papers

  1. . A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity. J Innate Immun. 2017;9(5):456-463. Epub 2017 Jun 27 PubMed.