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

Dionísio Pedro Amorim Neto; Beatriz Pelegrini Bosque; João Vitor Pereira de Godoy; Paulla Vieira Rodrigues; Dario Donoso Meneses; Katiane Tostes; Celisa Caldana Costa Tonoli; Hernandes Faustino de Carvalho; Christian González-Billault; Matheus de Castro Fonseca

doi:10.1016/j.isci.2022.103908

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

iScience. 2022 Feb 11;25(3):103908. doi: 10.1016/j.isci.2022.103908. eCollection 2022 Mar 18.

Authors

Dionísio Pedro Amorim Neto^{1

2}, Beatriz Pelegrini Bosque^{1

2}, João Vitor Pereira de Godoy^{1

2}, Paulla Vieira Rodrigues^{1

2}, Dario Donoso Meneses¹, Katiane Tostes¹, Celisa Caldana Costa Tonoli¹, Hernandes Faustino de Carvalho², Christian González-Billault^{3

4

5

6}, Matheus de Castro Fonseca^{1

2}

Affiliations

¹ Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 10000 Giuseppe Maximo Scolfaro St., 13083-100 Campinas, São Paulo, Brazil.
² Department of Structural and Functional Biology, State University of Campinas, Campinas, São Paulo, Brazil.
³ Department of Biology, Faculty of Sciences and Department of Neurosciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
⁴ Department of Neurosciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
⁵ Geroscience Center for Brain Health and Metabolism, Santiago, Chile.
⁶ The Buck Institute for Research on Aging, Novato, CA 94945, USA.

Abstract

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.

Keywords: Microbiome; Neuroscience.