Study of estrogen receptors mediated autophagy against tau toxicity in cell and zebrafish models

• Grant number: 16/20796-2
• Support Opportunities: Research Grants - Young Investigators Grants
• Duration: November 01, 2017 - January 31, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Rodrigo Portes Ureshino
• Grantee: Rodrigo Portes Ureshino
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
• Associated researchers: Catarina Segreti Porto ; Gustavo José da Silva Pereira ; Soraya Soubhi Smaili
• Associated grant(s): 20/04709-8 - Evaluation of potential therapeutically compounds for SARS-CoV-2: focus on estrogen-related compounds, autophagy modulators and ACE2, AP.R
• Associated scholarship(s): 21/11960-1 - Evaluation of estrogenic compounds in mitochondrial dysfunction and cellular metabolism in a tauopathy cell model, BP.IC; 21/01350-1 - Husbandry and handling of zebrafish model in a rack system, BP.TT; 19/20131-9 - Study of intracellular signalling and metabolism mediated by estrogen in a neurodegeneration cell model, BP.MS; + associated scholarships 19/19176-8 - Husbandry and handling of zebrafish model in a rack system, BP.TT; 19/11546-0 - Study of the estrogen-modulated autophagy in a neurodegeneration model by tau protein superexpression in zebrafish, BP.MS; 18/06260-8 - Study of cannabinoid compounds modulation in the autophagy mediated by TFEB in a cellular tauophathy model, BP.DR; 18/09925-0 - Establishment of a Hek-293 cell model to study the estrogenic signaling mediated by xenoestrogens in the autophagy activation: a link with Tauopathies cell models, BP.IC; 18/16719-8 - The role of estrogen receptors in autophagy in cellular model of Tauopathy, BP.DD; 17/23616-8 - Analysis of progestagen receptors-mediated autophagy against tau toxicity in cell model of tauopathy, BP.PD; 18/02762-9 - Evaluation of estrogen-mediated neuroprotection in cellular model of the tauopathy, BP.MS - associated scholarships

Abstract

Many studies have shown the effects of estrogens in neuroprotection in neurodegenerative processes, such as in Alzheimer's Disease. Furthermore, modulation of autophagy is one of the promising strategies for the treatment of dementias associated with the formation of protein aggregates, which occur in Tauopathies, where the main component is the tau protein. However, the role of estrogens in regulating autophagy has to be elucidated in the central nervous system. Thus, this project aims to investigate the involvement of estrogen receptors ER-alpha, ER-beta and GPER in the modulation of autophagy pathways, focusing on cellular protection in cell and animal models of neurodegenerative disease. In the first part of the project it will be established and characterized a cellular model of neurons overexpressing human tau protein. The autophagy induction mediated by activation/inhibition will be evaluated, searching for compounds that are able to reduce the protein accumulation. In parallel, it will be studied the intracellular signaling and bioenergetics modulated by activation/inhibition of estrogen receptors, by using pharmacological approaches, as well as knockout of estrogen receptors. In the second part of the project it will be used a Zebrafish model to study the role of estrogen receptors in the induction of autophagy in vivo, and subsequently the possible neuroprotective role against the human tau protein. Thus, considering that the regulation of estrogen receptor plays an important role in cytoprotection, its interrelation with the autophagy process can open new possibilities of combination therapy for dementia, as occurs in Alzheimer's Disease. (AU)

Scientific publications

(14)

(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)

NASCIMENTO, ANA CAROLINA; ERUSTES, ADOLFO G.; RECKZIEGEL, PATRICIA; BINCOLETTO, CLAUDIA; URESHINO, RODRIGO P.; PEREIRA, GUSTAVO J. S.; SMAILI, SORAYA S.. alpha-Synuclein Overexpression Induces Lysosomal Dysfunction and Autophagy Impairment in Human Neuroblastoma SH-SY5Y. Neurochemical Research, SEP 2020. (19/02821-8, 16/20796-2, 13/20073-2, 17/10863-7)

COSTA, ANGELICA JARDIM; LEMES, ROBERTHA MARIANA RODRIGUES; BARTOLOMEO, CYNTHIA SILVA; NUNES, TAMIRES ALVES; PEREIRA, GABRIELA CRUZ; OLIVEIRA, RAFAELA BRITO; GOMES, ALEXANDRE LOPES; SMAILI, SORAYA SOUBHI; MACIEL, RUI MONTEIRO DE BARROS; NEWSON, LOUISE; et al. Overexpression of estrogen receptor GPER1 and G1 treatment reduces SARS-CoV-2 infection in BEAS-2B bronchial cells. Molecular and Cellular Endocrinology, v. 558, p. 8-pg., 2022-12-01. (20/04709-8, 06/60402-1, 18/06088-0, 20/13480-4, 20/06153-7, 18/02762-9, 16/20796-2, 19/10922-9)

ERUSTES, ADOLFO GARCIA; D'ELETTO, MANUELA; GUARACHE, GABRIEL CICOLIN; URESHINO, RODRIGO PORTES; BINCOLETTO, CLAUDIA; DA SILVA PEREIRA, GUSTAVO JOSE; PIACENTINI, MAURO; SMAILI, SORAYA SOUBHI. Overexpression of alpha-synuclein inhibits mitochondrial Ca2+ trafficking between the endoplasmic reticulum and mitochondria through MAMs by altering the GRP75-IP3R interaction. Journal of Neuroscience Research, v. 99, n. 11, SEP 2021. (19/02821-8, 16/05580-3, 17/10863-7, 13/20073-2, 19/14722-4, 16/20796-2)

BARTOLOMEO, CYNTHIA SILVA; LEMES, ROBERTHA MARIANA RODRIGUES; MORAIS, RAFAEL LEITE; PERERIA, GABRIELA CRUZ; NUNES, TAMIRES ALVES; COSTA, ANGELICA JARDIM; MACIEL, RUI MONTEIRO DE BARROS; BRACONI, CARLA TORRES; MARICATO, JULIANA TERZI; JANINI, LUIZ MARIO RAMOS; et al. SARS-CoV-2 infection and replication kinetics in different human cell types: The role of autophagy, cellular metabolism and ACE2 expression. Life Sciences, v. 308, p. 13-pg., 2022-09-07. (20/04709-8, 06/60402-1, 20/06153-7, 20/13480-4, 20/08943-5, 16/20796-2, 19/10922-9)

VRECHI, TALITA A. M.; LEAO, ANDERSON H. F. F.; MORAIS, INGRID B. M.; ABILIO, VANESSA C.; ZUARDI, ANTONIO W.; HALLAK, JAIME EDUARDO C.; CRIPPA, JOSE ALEXANDRE; BINCOLETTO, CLAUDIA; URESHINO, RODRIGO P.; SMAILI, SORAYA S.; et al. Cannabidiol induces autophagy via ERK1/2 activation in neural cells. SCIENTIFIC REPORTS, v. 11, n. 1, MAR 8 2021. (18/06260-8, 19/02821-8, 19/14722-4, 17/10863-7, 16/20796-2)

SEIXAS, MARIA LUIZA G. A.; MITRE, LUCAS PARI; SHAMS, SHAHIN; LANZUOLO, GABRIEL BARBUGIAN; BARTOLOMEO, CYNTHIA SILVA; SILVA, EDUARDO A.; PRADO, CARLA MAXIMO; URESHINO, RODRIGO; STILHANO, ROBERTA SESSA. Unraveling Muscle Impairment Associated With COVID-19 and the Role of 3D Culture in Its Investigation. FRONTIERS IN NUTRITION, v. 9, p. 20-pg., 2022-02-10. (20/04709-8, 18/06088-0, 16/20796-2, 19/10922-9)

RODRIGUES LEMES, ROBERTHA MARIANA; COSTA, ANGELICA JARDIM; BARTOLOMEO, CYNTHIA SILVA; BASSANI, TAYSA BERVIAN; NISHINO, MICHELLE SAYURI; DA SILVA PEREIRA, GUSTAVO JOSE; SMAILI, SORAYA SOUBHI; DE BARROS MACIEL, RUI MONTEIRO; BRACONI, CARLA TORRES; DA CRUZ, EDGAR FERREIRA; et al. 17 beta-estradiol reduces SARS-CoV-2 infection in vitro. PHYSIOLOGICAL REPORTS, v. 9, n. 2, JAN 2021. (16/20796-2, 06/60402-1, 18/06088-0, 20/06153-7, 19/10922-9, 20/04709-8)

COSTA, ANGELICA JARDIM; ERUSTES, ADOLFO GARCIA; SINIGAGLIA, RITA; NEVES GIRARDI, CARLOS EDUARDO; DA SILVA PEREIRA, GUSTAVO JOSE; URESHINO, RODRIGO PORTES; SMAILI, SORAYA SOUBHI. Lack of Autophagy Induction by Lithium Decreases Neuroprotective Effects in the Striatum of Aged Rats. PHARMACEUTICS, v. 13, n. 2, FEB 2021. (17/10863-7, 12/08273-3, 16/20796-2, 13/20073-2, 13/20976-2)

URESHINO, RODRIGO PORTES; ERUSTES, ADOLFO GARCIA; BASSANI, TAYSA BERVIAN; WACHILEWSKI, PATRICIA; GUARACHE, GABRIEL CICOLIN; NASCIMENTO, ANA CAROLINA; COSTA, ANGELICA JARDIM; SMAILI, SORAYA SOUBHI; DA SILVA PEREIRA, GUSTAVO JOSE. The Interplay between Ca2+ Signaling Pathways and Neurodegeneration. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 20, n. 23, DEC 2019. (16/20796-2, 17/23616-8, 13/20073-2, 17/10863-7)

STILHANO, ROBERTA SESSA; COSTA, ANGELICA JARDIM; NISHINO, MICHELLE SAYURI; SHAMS, SHAHIN; BARTOLOMEO, CYNTHIA SILVA; BREITHAUPT-FALOPPA, ANA CRISTINA; SILVA, EDUARDO ALEXANDRE; RAMIREZ, ANA LOPEZ; PRADO, CARLA MAXIMO; URESHINO, RODRIGO PORTES. SARS-CoV-2 and the possible connection to ERs, ACE2, and RAGE: Focus on susceptibility factors. FASEB JOURNAL, v. 34, n. 11, p. 14103-14119, NOV 2020. (20/04709-8, 18/16719-8, 18/06088-0, 16/20796-2)

CIPRIANO DA SILVA, TAMIRIS REISSA; OLIVEIRA, RAFAELA BRITO; NICASTRO, ARTHUR LUIZ MIRANDA; URESHINO, RODRIGO PORTES; RAMINELLI, CRISTIANO. Total Synthesis of Aporphine Alkaloids via Benzyne Chemistry: Progress Towards a Late-Stage Enantioselective Hydrogenation and Neuroprotective Activity Evaluations. CHEMISTRYSELECT, v. 8, n. 36, p. 10-pg., 2023-09-26. (20/12530-8, 16/20796-2, 20/04709-8)

NASCIMENTO, ANA CAROLINA; ERUSTES, ADOLFO G.; RECKZIEGEL, PATRICIA; BINCOLETTO, CLAUDIA; URESHINO, RODRIGO P.; PEREIRA, GUSTAVO J. S.; SMAILI, SORAYA S.. alpha-Synuclein Overexpression Induces Lysosomal Dysfunction and Autophagy Impairment in Human Neuroblastoma SH-SY5Y. Neurochemical Research, v. 45, n. 11, p. 13-pg., 2020-09-11. (13/20073-2, 19/02821-8, 17/10863-7, 16/20796-2)

BASSANI, TAYSA BERVIAN; BARTOLOMEO, CYNTHIA SILVA; OLIVEIRA, RAFAELA BRITO; URESHINO, RODRIGO PORTES. Progestogen-Mediated Neuroprotection in Central Nervous System Disorders. Neuroendocrinology, v. 113, n. 1, p. 22-pg., 2023-01-01. (20/04709-8, 16/20796-2, 18/02762-9, 17/23616-8)

COSTA, ANGELICA JARDIM; OLIVEIRA, RAFAELA BRITO; WACHILEWSKI, PATRICIA; NISHINO, MICHELLE SAYURI; BASSANI, TAYSA BERVIAN; STILHANO, ROBERTA SESSA; CERUTTI, JANETE MARIA; NOZIMA, BRUNO; PORTO, CATARINA SEGRETI; DA SILVA PEREIRA, GUSTAVO JOSE; et al. Membrane estrogen receptor ERa activation improves tau clearance via autophagy induction in a tauopathy cell model. Brain Research, v. 1795, p. 16-pg., 2022-09-13. (19/02821-8, 20/04709-8, 19/14722-4, 16/20796-2, 17/23616-8, 17/10863-7, 18/16719-8, 18/02762-9)