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Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils
Published on: September 28, 2019
Gut microbiota produces biofilm-associated amyloids with potential for neurodegeneration
Ariadna Fernández-Calvet1, Leticia Matilla-Cuenca1, María Izco2
1Instituto de Agrobiotecnología (IDAB). CSIC-Gobierno de Navarra, Avenida Pamplona 123, Mutilva, 31192, Spain.
Abstract:
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.
Insights
Gut bacteria
Area of Science:
- Microbiology
- Neuroscience
- Gastroenterology
Background:
- Age-related neurodegenerative diseases and amyloid aggregation pose significant medical challenges.
- The gut microbiome's alterations are increasingly linked to neurological disorders' origins.
Purpose of the Study:
- To investigate the amyloidogenic potential of gut microbiota biofilm-associated proteins (BAPs).
- To explore the role of BAPs in synucleinopathies, such as Parkinson's disease.
Main Methods:
- Isolation and characterization of amyloid-like fibrils from human gut microbiota.
- Genetic analysis of BAP genes and their association with microbiome variability.
- In vitro studies using dopaminergic neurons and Caenorhabditis elegans models.
- In vivo studies involving inoculation of BAP fibrils into mouse brains.
Main Results:
- BAPs naturally form amyloid-like fibrils in the human gut microbiota.
- Abundance of certain BAP genes correlates with Parkinson's disease incidence.
- BAP-derived amyloids induce alpha-synuclein aggregation and compromise chaperone-mediated autophagy.
- BAP fibril inoculation in mice recapitulates key Parkinson's disease pathological features.
Conclusions:
- Gut microbiota BAPs are potent inducers of alpha-synuclein aggregation.
- BAP amyloids represent potential therapeutic targets and biomarkers for synucleinopathies.
- Microbiome-derived amyloids contribute to neurodegeneration, highlighting a gut-brain axis connection.
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