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

eLife

Pernilla Wittung-Stafshede¹  Istvan Horvath²  Viviana Gradinaru²  Sarkis K Mazmanian³  Neha Jain³  Rob Knight⁴  Justine W Debelius⁴  Stefan Janssen⁴  Brittany D Needham⁵  Mark S Ladinsky⁵  Timothy R Sampson⁵  Matthew Chapman⁵  Anastasiya Moiseyenko⁵  Taren Thron⁵  Collin Challis⁵  Gauri G Shastri⁵ 

[1] Department of Computer Science and Engineering, University of California, San Diego, San Diego, United States;Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden;Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States;Department of Pediatrics, University of California, San Diego, San Diego, United States;Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, United States;

关键词: microbiome;    alpha-synuclein;    Curli;   

DOI  :  10.7554/eLife.53111

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown