A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 11, 2020
- Source ID
- 10.7554/elife.53111
Entities
People
- Anastasiya Moiseyenko
- Brittany D Needham
- Collin Challis
- Gauri G Shastri
- Istvan Horvath
- Justine W. Debelius
- Mark S Ladinsky
- Matthew Chapman
- Neha Jain
- Pernilla Wittung-Stafshede
- Rob Knight
- Sarkis Mazmanian
- Stefan Janssen
- Taren Thron
- Timothy R. Sampson
- Viviana Gradinaru
Organizations
- California Institute of Technology
- Chalmers University of Technology
- Knut and Alice Wallenberg Foundation
- Larry L. Hillblom Foundation
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging
- Swedish Research Council
- United States Department of Defense
- University of California
- University of Michigan