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标题：Akkermansia muciniphila induces mitochondrial calcium overload and α -synuclein aggregation in an enteroendocrine cell line
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作者：Dionísio Pedro Amorim Neto ; Beatriz Pelegrini Bosque ; João Vitor Pereira de Godoy 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：3
页码：1-30
DOI：10.1016/j.isci.2022.103908
语种：English
出版社：Elsevier
摘要：SummaryThe gut microbiota influence neurodevelopment, modulate behavior, and contribute to neurodegenerative disorders. Several studies have consistently reported a greater abundance ofAkkermansia muciniphilain Parkinson disease (PD) fecal samples. Therefore, we investigated whetherA.muciniphila-conditioned medium (CM) could initiate α-synuclein (αSyn) misfolding in enteroendocrine cells (EEC) — a component of the gut epithelium featuring neuron-like properties. We found thatA.muciniphilaCM composition is influenced by the ability of the strain to degrade mucin. Ourin vitroexperiments showed that the protein-enriched fraction of mucin-free CM induces RyR-mediated Ca2+release and increased mitochondrial Ca2+uptake leading to ROS generation and αSyn aggregation. Oral administration ofA. muciniphilacultivated in the absence of mucin to mice led to αSyn aggregation in cholecystokinin (CCK)-positive EECs but no motor deficits were observed. Noteworthy, buffering mitochondrial Ca2+reverted the damaging effects observed. These molecular insights offer evidence that bacterial proteins can induce αSyn aggregation in EECs.Graphical abstractDisplay OmittedHighlights•Gut bacteriumAkkermansia muciniphilais increased in patients with Parkinson disease•A. muciniphila-conditioned medium induces mitochondrial Ca2+overload in EECs•Mitochondrial Ca2+overload leads to ROS generation and αSyn aggregationin vitro•Buffering mitochondrial Ca2+inhibitsA. muciniphila-induced αSyn aggregationNeuroscience; Microbiome