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

Author(s)

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

• Document type: Journal article
• Source: ISCIENCE; v. 25, n. 3, p. 30-pg., 2022-03-18.

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 alpha-synuclein (alpha Syn) 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 ofmucin-free CM induces RyR-mediated Ca2+ release and increased mitochondrial Ca2+ uptake leading to ROS generation and aSyn aggregation. Oral administration of A. muciniphila cultivated in the absence of mucin to mice led to alpha Syn 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 alpha Syn aggregation in EECs. (AU)

• FAPESP's process: 18/20014-0 - The gut-brain connection: role of the gut microbioma in the outcome and development of the sporadic Parkinson's disease
• Grantee: Matheus de Castro Fonseca
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/24511-0 - The role of LRRK2 and Rab GTPases in the neurodegeneration during sporadic Parkinson's Disease
• Grantee: Beatriz Pelegrini Bosque
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 14/50938-8 - INCT 2014: in Photonics Applied to Cell Biology
• Grantee: Hernandes Faustino de Carvalho
• Support Opportunities: Research Projects - Thematic Grants