eLife (Feb 2020)

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

  • Timothy R Sampson,
  • Collin Challis,
  • Neha Jain,
  • Anastasiya Moiseyenko,
  • Mark S Ladinsky,
  • Gauri G Shastri,
  • Taren Thron,
  • Brittany D Needham,
  • Istvan Horvath,
  • Justine W Debelius,
  • Stefan Janssen,
  • Rob Knight,
  • Pernilla Wittung-Stafshede,
  • Viviana Gradinaru,
  • Matthew Chapman,
  • Sarkis K Mazmanian

DOI
https://doi.org/10.7554/eLife.53111
Journal volume & issue
Vol. 9

Abstract

Read online

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.

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