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

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

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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