Akkermansia muciniphila secretome promotes α-synuclein aggregation in enteroendocrine cells

Abstract

ABSTRACTThe notion that the gut microbiota play a role in neurodevelopment, behavior and outcome of neurodegenerative disorders is recently taking place. A number of studies have consistently reported a greater abundance of Akkermansia muciniphila in Parkinson’s disease (PD) fecal samples. Nevertheless, a functional link between A.muciniphila and sporadic PD remained unexplored. Here, we investigated whether A.muciniphila secretome could initiate the misfolding process of α-synuclein (αSyn) in enteroendocrine cells (EECs), which are part of the gut epithelium and possess many neuron-like properties. We found that A.muciniphila secretome is directly modulated by mucin, induces intracellular calcium (Ca2+) release, and causes increased mitochondrial Ca2+ uptake in EECs, which in turn leads to production of reactive oxygen species (ROS) and αSyn aggregation. However, these events were efficiently inhibited once we buffered mitochondrial Ca2+. Thereby, these molecular insights provided here offer evidence that bacterial secretome is capable of inducing αSyn aggregation in enteroendocrine cells.SYNOPSIS FIGURE DESCRIPTIONThe secretome isolated from the commensal gut bacterium Akkermansia muciniphila triggers intracellular Ca2+ signaling in enteroendocrine cells, leading to increased mitochondrial Ca2+ uptake. Mitochondrial Ca2+ overload leads to ROS generation culminating with αSyn phosphorylation and aggregation (left panel). All these events were inhibited once mitochondrial Ca2+ is buffered (right panel).Gram-negative gut bacterium Akkermansia muciniphila is consistently found more abundant in Parkinson’s disease patients.Akkermansia muciniphila protein secretome composition is directly modulated by mucin and induces an IP3-independent endoplasmic reticulum (ER)-calcium release in enteroendocrine cells.This Ca2+ release is triggered by direct activation of Ryanodine Receptors leading to increased mitochondrial Ca2+ uptake.Mitochondrial Ca2+ overload leads to ROS generation culminating with αSyn aggregation.Buffering mitochondrial Ca2+ efficiently inhibits A.muciniphila-induced αSyn aggregation in enteroendocrine cells.