Akkermansia muciniphila secretome promotes α-synuclein aggregation in enteroendocrine cells

ABSTRACT The 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 (Ca 2+ ) release, and causes increased mitochondrial Ca 2+ 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 Ca 2+ . Thereby, these molecular insights provided here offer evidence that bacterial secretome is capable of inducing αSyn aggregation in enteroendocrine cells. SYNOPSIS FIGURE DESCRIPTION The secretome isolated from the commensal gut bacterium Akkermansia muciniphila triggers intracellular Ca 2+ signaling in enteroendocrine cells, leading to increased mitochondrial Ca 2+ uptake. Mitochondrial Ca 2+ overload leads to ROS generation culminating with αSyn phosphorylation and aggregation (left panel). All these events were inhibited once mitochondrial Ca 2+ 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 IP 3 -independent endoplasmic reticulum (ER)-calcium release in enteroendocrine cells. This Ca 2+ release is triggered by direct activation of Ryanodine Receptors leading to increased mitochondrial Ca 2+ uptake. Mitochondrial Ca 2+ overload leads to ROS generation culminating with αSyn aggregation. Buffering mitochondrial Ca 2+ efficiently inhibits A.muciniphila- induced αSyn aggregation in enteroendocrine cells.