Gut microbiota produces biofilm-associated amyloids with potential for neurodegeneration.
Ariadna Fernández-CalvetLeticia Matilla-CuencaMaria IzcoSusanna NavarroMiriam SerranoSalvador VenturaJavier BlesaMaite HerráizGorka Alkorta-AranburuSergio GaleraRuiz De Los Mozos IgorMaria Luisa MansegoAlejandro Toledo-AranaLydia Alvarez-ErvitiJaione VallePublished in: Nature communications (2024)
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.
Keyphrases
- wild type
- endothelial cells
- pseudomonas aeruginosa
- staphylococcus aureus
- genome wide
- candida albicans
- cell death
- risk factors
- signaling pathway
- dna methylation
- endoplasmic reticulum stress
- metabolic syndrome
- climate change
- biofilm formation
- cystic fibrosis
- antibiotic resistance genes
- heat shock protein
- high fat diet induced
- wastewater treatment
- induced pluripotent stem cells
- cerebral ischemia
- pluripotent stem cells