Could Bacterial Amyloid Trigger Parkinson’s Pathology?

What kick-starts the aggregation of pathological proteins in neurodegenerative disease? In the October 6 Scientific Reports, researchers led by Robert Friedland at the University of Louisville School of Medicine, Kentucky, present more evidence that microorganisms might play a role. Feeding aging rats with Escherichia coli that produces its own amyloid protein accelerated the deposition of α-synuclein in both the gut and the brain, they report. The new data bolster the hypothesis that Parkinson’s disease can start in the gut, and that amyloidogenic proteins can “cross-seed,” a process where one type of misfolded protein causes another to misfold. “There are now substantial reasons to believe that our microbiota may influence neurodegenerative diseases,” Friedland told Alzforum. Because the composition of the gut microbiome can be altered by diet or other environmental factors, this research might open up new therapeutic approaches, he suggested.

Others found the data intriguing as well. “The possibility of such cross-seeding events in the gut … may offer a novel target for prevention and/or pharmacological treatment. However, additional studies are needed to understand these molecular interactions, including identifying the exact nature of the propagating α-synuclein species,” Martin Ingelsson and Joakim Bergström at Uppsala University, Sweden, wrote to Alzforum (see full comment below). Jeffrey Kordower at Rush University, Chicago, noted, “The idea that microbiota influence brain function has been around for many years, but now it’s accumulating empirical data. This is an excellent, exciting paper that will stimulate more research.”

Cross-Seeding?

Worms fed on bacteria that produce amyloid (left) developed many more and larger α-synuclein inclusions (green) than did worms eating control bacteria (right). [Courtesy of Chen et al., Scientific Reports.]

The concept that microbiota could initiate degeneration has been gradually taking hold. Heiko Braak and Kelly Del Tredici at the University of Ulm, Germany, first documented in 2003 how Parkinson’s pathology might begin in intestinal neurons, and from there work its way up to the brain, perhaps triggered by a pathogen such as a virus (see July 2011 series). A recent study from Finland tied differences in the gut microbiome to a diagnosis of Parkinson’s as well as the severity of movement problems in patients (see Scheperjans et al., 2015). Pathogens have also been implicated in Alzheimer’s disease. Researchers at Massachusetts General Hospital recently reported that Aβ’s normal function is to fight infection by trapping microbes in its fibrils, suggesting that this process might initiate pathological aggregation (see May 2016 news). In keeping with this, antibiotic treatment lessens amyloid pathology in AD model mice (see Minter et al., 2016). 

Friedland wondered if bacteria might stimulate neurodegenerative pathology through cross-seeding. Many bacteria found in people produce amyloids, and these proteins possess structural similarities to human pathological aggregates (see Larsen et al., 2007; Hufnagel et al., 2013; Friedland, 2015). Other studies have shown that different pathological proteins can stimulate each other’s aggregation, such as prions and TDP-43 triggering Aβ fibrillization, and α-synuclein seeding tau tangles (see Apr 2010 news; Jul 2013 news; Sep 2014 news). 

To test the effect of bacterial amyloid, second author Vilius Stribinskis turned to E. coli, which make an amyloidogenic protein called curli. Stribinskis and colleagues squirted a solution containing this bacteria into the mouths of 2-year-old wild-type rats once per week for two to three months. About one dozen rats received wild-type E. coli, another dozen swallowed mutant E. coli that lacked the ability to make curli, and nine more rats received vehicle only. When the animals were sacrificed and analyzed, those that had ingested normal E. coli had about 10 times more α-synuclein deposits in intestinal neurons, and about 50 percent more in hippocampal and striatal neurons, than the other two groups. Notably, the gut deposits dissolved upon treatment with proteinase K, suggesting they were not aggregated, whereas hippocampal α-synuclein deposits resisted this treatment. Inflammation also surged in the brains of rats that ate wild-type E. coli, with markers of microgliosis and astrogliosis up 50 to 100 percent. The paper does not report if any bacteria colonized the brain.

Would the same thing occur in animal models of neurodegenerative disease? First author Shu Chen at Case Western Reserve University, Cleveland, fed wild-type and mutant E. coli to roundworms that expressed fluorescently tagged human α-synuclein in their body wall muscles. Worms that ate wild-type E. coli for three days developed about twice as many α-synuclein deposits in their muscles as did those eating control bacteria, again supporting the idea that bacterial amyloid can initiate deposition (see image above).

How curli amyloid stimulates α-synuclein aggregation is not yet clear, but Friedland favors the idea that it occurs through cross-seeding and subsequent propagation of misfolded proteins from the gut to the brain through the vagus nerve. Notably, one of the first brain regions to succumb to Parkinson’s pathology is the dorsal motor nucleus of the vagus nerve in the medulla. In ongoing work, Friedland is testing whether these α-synuclein deposits affect behavior in aged rats. He is also examining how bacterial amyloids affect aggregation of other proteins in mouse models of different neurodegenerative diseases.

Friedland will also pursue studies in people. He is studying differences in the bacterial population in Parkinson’s patients, and also looking at how common bacterial amyloids are in the human body. One previous study reported the presence of curli aggregates in people, but the subject has received almost no other investigation, Friedland noted (see Bokranz et al., 2005). 

Kordower suggested it would be interesting to track the time course of α-synuclein deposition in rats, to see if it follows anatomical pathways through the body and brain. He also wonders whether neuroinflammation precedes or trails aggregation. “That is fertile ground for future studies,” he noted. Overall, he found the work particularly exciting because it showed robust acceleration of α-synuclein deposition in wild-type rats, hinting this could be a mechanism for sporadic disease. The microbiome might contribute to many other neurodegenerative diseases besides Parkinson’s, Kordower suggested. The fact that amyloids can cross-seed many other types of aggregate might help explain the frequency of mixed pathology in brain disease, he speculated. “Studying the microbiome is one of the most exciting areas in neurodegenerative disease right now,” he told Alzforum.—Madolyn Bowman Rogers

Comments

  1. The study by Chen et al. offers a possible explanation as to how Parkinson’s disease (PD)-related pathology may appear in the gut and subsequently spread to the CNS. By using two different animal models, rats and nematodes, the authors found that the presence of a certain E.coli strain that produces an amyloidogenic protein, curli, seems to trigger aggregation of α-synuclein, the protein forming amyloid aggregates in the PD brain.

    This investigation builds on the observation that Parkinson’s patients frequently display deposition of α-synuclein in the colon mucosa (Braak et al., 2006) and that rats that had been injected with α-synuclein in the gut wall were found to develop pathology in the dorsal motor nucleus of the vagus nerve (Holmqvist et al., 2014). 

    Seeding and cross-seeding between proteins with amyloidogenic properties have been previously described. For example, certain forms of both amyloid-β and α-synuclein can both seed themselves and cross-seed each other (Ono et al., 2012). As for bacterial amyloids, they have also been suggested to have cross-seeding properties. For example, curli fibrils have been shown to cross-seed serum amyloid A (Lundmark et al., 2005), a protein with an amphipathic helical structure similar to α-synuclein.

    Taken together, the current study and previous observations indicate that specific tertiary structures can make certain proteins capable of inducing formation of pathogenic amyloids. The possibility of such cross-seeding events in the gut, resulting in the formation and subsequent transport of α-synuclein aggregates to the Parkinson’s brain, may offer a novel target for prevention and/or pharmacological treatment. However, additional studies are needed to understand these molecular interactions, including the more exact nature of the propagating α-synuclein species.

    References:

    Braak H, De Vos RA, Bohl J, Del Tredici K. Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett. 2006 Mar 20;396(1):67-72. PubMed.

    Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Björklund T, Wang ZY, Roybon L, Melki R, Li JY. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014 Dec;128(6):805-20. Epub 2014 Oct 9 PubMed.

    Ono K, Takahashi R, Ikeda T, Yamada M. Cross-seeding effects of amyloid β-protein and α-synuclein. J Neurochem. 2012 Sep;122(5):883-90. PubMed.

    Lundmark K, Westermark GT, Olsén A, Westermark P. Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism. Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6098-102. PubMed.

    View all comments by Martin Ingelsson View all comments by Joakim Bergstrom

  2. I thought the paper was interesting, potentially the first example of cross-seeding that would provide an explanation for at least some cases of idiopathic disease. The outstanding issue is whether it is actually cross-seeding, or if the curli protein interferes with protein degradation promoting persistence of misfolded proteins generally. Some type of in vitro conversion experiment would help answer this.

    View all comments by Robert Petersen

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References

Series Citations

  1. A Contentious Hypothesis About Where and How PD Starts

News Citations

  1. Like a Tiny Spider-Man, Aβ May Fight Infection by Cocooning Microbes
  2. Amyloid and Prions—Co-Conspirators in Disease?
  3. An Extra Strain on the Brain—α-Synuclein Seeds Tau Aggregation
  4. Does TDP-43 Oligomerize and Coax Aβ to Do the Same?

Paper Citations

  1. Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola-Rautio J, Pohja M, Kinnunen E, Murros K, Auvinen P. Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord. 2015 Mar;30(3):350-8. Epub 2014 Dec 5 PubMed.
  2. Minter MR, Zhang C, Leone V, Ringus DL, Zhang X, Oyler-Castrillo P, Musch MW, Liao F, Ward JF, Holtzman DM, Chang EB, Tanzi RE, Sisodia SS. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer's disease. Sci Rep. 2016 Jul 21;6:30028. PubMed.
  3. Larsen P, Nielsen JL, Dueholm MS, Wetzel R, Otzen D, Nielsen PH. Amyloid adhesins are abundant in natural biofilms. Environ Microbiol. 2007 Dec;9(12):3077-90. PubMed.
  4. Hufnagel DA, Tükel C, Chapman MR. Disease to dirt: the biology of microbial amyloids. PLoS Pathog. 2013;9(11):e1003740. Epub 2013 Nov 21 PubMed.
  5. Friedland RP. Mechanisms of molecular mimicry involving the microbiota in neurodegeneration. J Alzheimers Dis. 2015;45(2):349-62. PubMed.
  6. Bokranz W, Wang X, Tschäpe H, Römling U. Expression of cellulose and curli fimbriae by Escherichia coli isolated from the gastrointestinal tract. J Med Microbiol. 2005 Dec;54(Pt 12):1171-82. PubMed.

Further Reading

Primary Papers

  1. Chen SG, Stribinskis V, Rane MJ, Demuth DR, Gozal E, Roberts AM, Jagadapillai R, Liu R, Choe K, Shivakumar B, Son F, Jin S, Kerber R, Adame A, Masliah E, Friedland RP. Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans. Sci Rep. 2016 Oct 6;6:34477. PubMed.

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