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The gut-brain connection: role of the gut microbioma in the outcome and development of the sporadic Parkinson's Disease

Grant number: 18/20014-0
Support type:Regular Research Grants
Duration: February 01, 2019 - January 31, 2021
Field of knowledge:Biological Sciences - Morphology
Principal Investigator:Matheus de Castro Fonseca
Grantee:Matheus de Castro Fonseca
Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil
Assoc. researchers:Carlos Sato Baraldi Dias ; Christian Gonzalez-Billault ; Cristina Guatimosim Fonseca ; Marjorie Christine Paule Bruder

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disease with devastating clinical manifestations. In PD, neuronal death is associated with intracellular accumulation of aggregated ±-synuclein (a-syn), a synaptic protein, forming structures known as Lewy bodies. The disease is found in two main forms: familial PD, comprehending 10% of the cases; and sporadic PD, comprehending 90% of all cases. Although the cause of sporadic PD is not completely understood, abundant pathological and clinical evidences show that misfolded ±-syn is found in enteric nerves before it appears in the brain. Thereby, this might suggest a hypothesis in which one possible cause of sporadic PD pathology is the misfolding and accumulation of a-syn in the gut, its migration throughout peripheric nerves and spreading to the central nervous system via cell-to-cell prion-like propagation, since misfolded a-synuclein initiates misfolding of native a-syn in recipient cells (seed hypothesis). It was recently shown that enteroendocrine cells (EECs), which are part of the gut epithelium, also possess many neuron-like properties and a direct connection to enteric nerves. In addition, since EECs face the gut lumen, these cells are in constant interaction with the gut microbiome, which might regulate much of their physiological and pathological processes. The gut/nutrient-centric nature of human evolutionary process proposes an important role for gut-associated microbiota in the maintenance of homeostasis and human health. Recent advances in microbiome research suggest that gastrointestinal microbiota might play an important role in pathogenesis of neurodegenerative disorders such as PD and also multiple sclerosis (MS). In fact, it was found that two bacteria groups, Acinetobacter and Akkermansia, were four times more abundant in MS patients than in individuals with no disease. Another group, Parabacteroides, was four times more abundant in healthy people. Therefore, the EECs, by their neuronal connection and interaction with the gut microbiome, might play a critical role in transmitting PD pathology from the gut to the brain. Therefore, understanding how the microbiome can influence the aggregation of ±-syn and how these amyloids are internalized by gut peripheric neurons will shed new light on innovative clinical interventions and drug discovery.This work will gather the efforts of national and international researchers with great experience in neurobiology, with the aim of exploring, in an unprecedented way in the country, to my knowledge, the influence of the microbioma on the misfolding of a-syn in intestinal cells and how this protein is able to reach peripheral nerve endings and migrate to ascending levels of the nervous system. (AU)

Scientific publications (5)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LEMOS, FERNANDA DE OLIVEIRA; FRANCA, ANDRESSA; MELO LIMA FILHO, ANTONIO CARLOS; FLORENTINO, RODRIGO M.; SANTOS, MARCONE LOIOLA; MISSIAGGIA, DABNY G.; LIBANIO RODRIGUES, GISELE OLINTO; DIAS, FELIPE FERRAZ; SOUZA PASSOS, INGREDY BEATRIZ; TEIXEIRA, MAURO M.; DE FARIA ANDRADE, ANTONIO MARCIO; LIMA, CRISTIANO XAVIER; TEIXEIRA VIDIGAL, PAULA VIEIRA; COSTA, VIVIAN VASCONCELOS; FONSECA, MATHEUS CASTRO; NATHANSON, MICHAEL H.; LEITE, M. FATIMA. Molecular Mechanism for Protection Against Liver Failure in Human Yellow Fever Infection. HEPATOLOGY COMMUNICATIONS, v. 4, n. 5, p. 657-669, MAY 2020. Web of Science Citations: 0.
NANI, V, JOAO; FONSECA, MATHEUS C.; ENGI, SHEILA A.; PERILLO, MAYARA G.; DIAS, CARLOS S. B.; GAZARINI, MARCOS L.; KORTH, CARSTEN; CRUZ, FABIO C.; HAYASHI, MIRIAN A. F. Decreased nuclear distribution nudE-like 1 enzyme activity in an animal model with dysfunctional disrupted-in-schizophrenia 1 signaling featuring aberrant neurodevelopment and amphetamine-supersensitivity. JOURNAL OF PSYCHOPHARMACOLOGY, v. 34, n. 4 JAN 2020. Web of Science Citations: 0.
LEITE SCHETINO, LUANA PEREIRA; FONSECA, MATHEUS DE CASTRO; SIMAO MAGALHAES GOMES, MATHEUS PROENCA; COSTA VALADAO, PRISCILA APARECIDA; DE CAMARGO, WALLACE LUCIO; RODRIGUES, HERMANN ALECSANDRO; ANDRADE, JESSICA NEVES; ARANTES-COSTA, FERNANDA MAGALHAES; NAVES, LIGIA ARAUJO; PRADO, CARLA MAXIMO; PRADO, VANIA FERREIRA; MAXIMO PRADO, MARCO ANTONIO; GUATIMOSIM, CRISTINA. Evaluation of the neuromuscular junction in a middle-aged mouse model of congenital myasthenic syndrome. MUSCLE & NERVE, v. 60, n. 6, p. 790-800, DEC 2019. Web of Science Citations: 0.
DIAS, CARLOS SATO BARALDI; AMORIM NETO, DIONISIO PEDRO; BARALDI, GIOVANNI LENZI; FONSECA, MATHEUS DE CASTRO. Comparative analysis of sample preparation protocols of soft biological tissues for morphometric studies using synchrotron-based X-ray microtomography. JOURNAL OF SYNCHROTRON RADIATION, v. 26, n. 6, p. 2013-2023, NOV 1 2019. Web of Science Citations: 0.
DOS SANTOS, KEMPER NUNES; FLORENTINO, RODRIGO M.; FRANCA, ANDRESSA; MELO LIMA FILHO, ANTONIO CARLOS; DOS SANTOS, MARCONE LOIOLA; MISSIAGGIA, DABNY; FONSECA, MATHEUS DE CASTRO; COSTA, IGOR BRASIL; TEIXEIRA VIDIGAL, PAULA VIEIRA; NATHANSON, MICHAEL H.; LEMOS, FERNANDA DE OLIVEIRA; FATIMA LEITE, M. Polymorphism in the Promoter Region of NFE2L2 Gene Is a Genetic Marker of Susceptibility to Cirrhosis Associated with Alcohol Abuse. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 20, n. 14 JUL 2 2019. Web of Science Citations: 0.

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