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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  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 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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  1. Could Bacterial Amyloid Trigger Parkinson’s Pathology?