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

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

doi:10.7554/elife.53111

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.

Highlights

The accumulation and aggregation of amyloid proteins occurs during many neurodegenerative diseases
Synucleinopathies are one family of amyloid disease, which includes Parkinson’s disease (PD), Lewy Body disease (LBD), and Multiple System Atrophy (MSA). Central to their pathogenesis is the accumulation of the neuronal protein a-Synuclein into insoluble amyloid aggregations, which leads to inflammation and neuronal dysfunction (Jucker and Walker, 2013; Brettschneider et al, 2015). aSyn aggregation can contribute to the death of dopaminergic neurons in specific brain regions, resulting in motor symptoms (Poewe et al, 2017)
Prior findings in germ-free Thy1-aSyn mice suggest that an unidentified member(s) of the gut microbiome may be pathogenic in this mouse model (Sampson et al, 2016)

Summary

Introduction

The accumulation and aggregation of amyloid proteins occurs during many neurodegenerative diseases. Synucleinopathies are one family of amyloid disease, which includes Parkinson’s disease (PD), Lewy Body disease (LBD), and Multiple System Atrophy (MSA). Central to their pathogenesis is the accumulation of the neuronal protein a-Synuclein (aSyn) into insoluble amyloid aggregations, which leads to inflammation and neuronal dysfunction (Jucker and Walker, 2013; Brettschneider et al, 2015). Clinical and epidemiological data suggest that accumulation of aSyn aggregates may first occur at peripheral sites, such as the olfactory epithelium or gastrointestinal (GI) tract, before spreading to the brain (Braak et al, 2003).

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