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Akkermansia muciniphila induces mitochondrial calcium overload and α -synuclein aggregation in an enteroendocrine cell line

2022; Cell Press; Volume: 25; Issue: 3 Linguagem: Inglês

10.1016/j.isci.2022.103908

2589-0042

Dionísio Pedro Amorim Neto, Beatriz Pelegrini Bosque, João Vitor Pereira de Godoy, Paulla Vieira Rodrigues, Dario Donoso Meneses, Katiane Tostes, C.C.C. Tonoli, Hernandes F. Carvalho, Christian González‐Billault, Matheus de Castro Fonseca,

Tryptophan and brain disorders

The gut microbiota influence neurodevelopment, modulate behavior, and contribute to neurodegenerative disorders. Several studies have consistently reported a greater abundance of Akkermansia muciniphila in Parkinson disease (PD) fecal samples. Therefore, we investigated whether A.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 that A. muciniphila CM composition is influenced by the ability of the strain to degrade mucin. Our in vitro experiments 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 of A. muciniphila cultivated 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.