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 similar to 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 alpha-synuclein (alpha Syn), we reveal that colonization with curli-producing Escherichia coli promotes alpha Syn pathology in the gut and the brain. Curli expression is required for E. coli to exacerbate alpha Syn-induced behavioral deficits, including intestinal and motor impairments. Purified curli subunits accelerate alpha Syn 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 alpha Syn aggregation and disease in the gut and the brain.