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Published February 11, 2020 | Supplemental Material + Published
Journal Article Open

A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice


Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated with neurodegenerative diseases. While genetic and environmental factors can influence amyloid formation, molecular triggers and/or facilitators are not well defined. Growing evidence suggests that non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. While humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli are cell surface amyloid proteins abundantly expressed by certain gut bacteria. In mice overexpressing the human amyloid α-synuclein (αSyn), we reveal that colonization with curli-producing Escherichia coli promotes αSyn pathology in the gut and the brain. Curli expression is required for E. coli to exacerbate αSyn-induced behavioral deficits, including intestinal and motor impairments. Purified curli subunits accelerate αSyn aggregation in biochemical assays, while oral treatment of mice with a gut-restricted amyloid inhibitor prevents curli-mediated acceleration of pathology and behavioral abnormalities. We propose that exposure to microbial amyloids in the gastrointestinal tract can accelerate αSyn aggregation and disease in the gut and the brain.

Additional Information

© 2020 Sampson et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received: 28 October 2019; Accepted: 23 January 2020; Published: 11 February 2020. We thank Drs. E Hsiao, M Sampson, S Campbell, D Yamashita, D Donabedian, and members of the SKM laboratory for helpful critiques and review of this manuscript. We are grateful to J Paramo, S Estrada, K Ly and the Caltech OLAR staff for animal care husbandry, and Y Garcia-Flores (Caltech) for technical support. Electron micrographs of amyloids were generated at the Microscopy and Imaging Analysis Laboratory Core at the University of Michigan. Fluorescent imaging and image analysis were performed in the Caltech Biological Imaging Facility, with the support of the Caltech Beckman Institute and the Arnold and Mabel Beckman Foundation. TRS was a Larry L Hillblom Foundation postdoctoral fellow. This project was supported by funds from the Heritage Medical Research Institute to VG and SKM; the Knut and Alice Wallenberg Foundation and Swedish Research Council to PW-S; the National Institutes of Health grants AG054101 (CC), GM118651 (MRC) and NS085910 (SKM); Axial Biotherapeutics to SKM; and the Department of Defense grant PD160030 to SKM. Data availability: All data generated or analysed during this study are included in the manuscript and supporting files. Source data files and statistical output for all figures have been provided. Author contributions: Timothy R Sampson, Conceptualization, Investigation, Visualization; Collin Challis, Neha Jain, Anastasiya Moiseyenko, Mark S Ladinsky, Istvan Horvath, Investigation, Visualization; Gauri G Shastri, Brittany D Needham, Investigation; Taren Thron, Resources, Investigation; Justine W Debelius, Stefan Janssen, Formal analysis; Rob Knight, Viviana Gradinaru, Supervision; Pernilla Wittung-Stafshede, Matthew Chapman, Sarkis K Mazmanian, Conceptualization, Supervision. Competing interests: Timothy R Sampson: has intellectual property pending in relationship to the content of this manuscript, US Patent App. 15/893,456 and 16/302,321. Matthew Chapman: a member of the Scientific Advisory Board of Axial Biotherapeutics. Sarkis K Mazmanian: has financial interest in Axial Biotherapeutics. Has intellectual property pending in relationship to the content of this manuscript, US Patent App. 15/893,456 and 16/302,321. The other authors declare that no competing interests exist. Ethics: Animal experimentation: All animal husbandry and experiments were approved by the California Institute of Technology's Institutional Animal Care and Use Committee (IACUC) under protocol #1707.

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