Gut microbiota produces biofilm-associated amyloids with potential for neurodegeneration

• Published in: Nature communications Vol. 15; no. 1; pp. 4150 - 19
• Main Authors: Fernández-Calvet, Ariadna, Matilla-Cuenca, Leticia, Izco, María, Navarro, Susanna, Serrano, Miriam, Ventura, Salvador, Blesa, Javier, Herráiz, Maite, Alkorta-Aranburu, Gorka, Galera, Sergio, Ruiz de los Mozos, Igor, Mansego, María Luisa, Toledo-Arana, Alejandro, Alvarez-Erviti, Lydia, Valle, Jaione
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 14/1; 14/34; 14/63; 49/23; 59; 631/326/2565/2134; 631/326/46; 64; 64/11; 64/60; 82/1; 82/29; 82/51; 82/80; Age; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Amyloid - metabolism; Amyloidogenesis; Animals; Autophagy; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biofilms; Biofilms - growth & development; Biomarkers; Brain - metabolism; Brain - pathology; Caenorhabditis elegans - metabolism; Caenorhabditis elegans - microbiology; Digestive system; Dopamine receptors; Dopaminergic Neurons - metabolism; Fibrils; Gastrointestinal Microbiome; Gastrointestinal tract; Genes; Genomes; Gut microbiota; Humanities and Social Sciences; Humans; Inoculation; Intestinal microflora; Intestine; Mice; Mice, Inbred C57BL; Microbiomes; Microbiota; Microorganisms; Movement disorders; multidisciplinary; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Neurological diseases; Parkinson Disease - metabolism; Parkinson Disease - microbiology; Parkinson Disease - pathology; Parkinson's disease; Proteins; Science; Science (multidisciplinary); Synuclein; Synucleinopathies - metabolism; Synucleinopathies - pathology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48309-x

Age-related neurodegenerative diseases involving amyloid aggregation remain one of the biggest challenges of modern medicine. Alterations in the gastrointestinal microbiome play an active role in the aetiology of neurological disorders. Here, we dissect the amyloidogenic properties of biofilm-associated proteins (BAPs) of the gut microbiota and their implications for synucleinopathies. We demonstrate that BAPs are naturally assembled as amyloid-like fibrils in insoluble fractions isolated from the human gut microbiota. We show that BAP genes are part of the accessory genomes, revealing microbiome variability. Remarkably, the abundance of certain BAP genes in the gut microbiome is correlated with Parkinson’s disease (PD) incidence. Using cultured dopaminergic neurons and Caenorhabditis elegans models, we report that BAP-derived amyloids induce α-synuclein aggregation. Our results show that the chaperone-mediated autophagy is compromised by BAP amyloids. Indeed, inoculation of BAP fibrils into the brains of wild-type mice promote key pathological features of PD. Therefore, our findings establish the use of BAP amyloids as potential targets and biomarkers of α-synucleinopathies. The microbiota of the intestinal tract is considered a large biofilm formed by myriads bacteria that have a considerable impact in health and disease. Here, the authors show that biofilm-associated proteins from intestinal microbiota form amyloid-like structures that exacerbate alpha-synuclein pathologies.