Sobrecarga de cálcio mitocondrial induzida pelo meio condicionado de Akkermansia muciniphila leva à agregação de alfa-sinucleina in um modelo de célula enteroendócrina.

• Processo: 22/01166-9
• Modalidade de apoio: Auxílio à Pesquisa - Publicações científicas - Artigo
• Data de Início da vigência: 01 de abril de 2022
• Data de Término da vigência: 30 de setembro de 2022
• Área do conhecimento: Ciências Biológicas - Morfologia - Citologia e Biologia Celular
• Pesquisador responsável: Hernandes Faustino de Carvalho
• Beneficiário: Hernandes Faustino de Carvalho
• Instituição Sede: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brasil
• Assunto(s): Akkermansia muciniphila
• Palavra(s)-Chave do Pesquisador: Akkermansia muciniphila | alpha synuclein | célula neuroendócrina | protein aggregation | cell microbiota interactions

Resumo

The notion that the gut microbiota plays 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 conditioned medium could initiate the misfolding process of ±-synuclein (±Syn) in enteroendocrine cell (EEC) model, which are part of the gut epithelium and possess many neuron-like properties. We found that A. muciniphila conditioned medium (CM) composition is influenced by the ability of the strain to degrade and utilize mucin. In addition, our in vitro experiments showed that only the protein-enriched fraction of mucin-free CM induces Ryanodine receptor (RyR)-mediated intracellular calcium (Ca2+) release and causes increased mitochondrial Ca2+ uptake in EECs, which in turn leads to production of reactive oxygen species (ROS) and ±Syn aggregation. Indeed, oral administration of A. muciniphila cultivated in the absence of mucin to aged mice also led to ±Syn aggregation in cholecystokinin (CCK)-positive EECs but no motor deficits were observed. Noteworthy, buffering mitochondrial Ca2+ in vitro reverted all the damaging effects observed. Thereby, these molecular insights provided here offer evidence that bacterial proteins are capable of inducing ±Syn aggregation in EECs. (AU)