The role of lysine(K)-deacetylases on mitochondrial disorders's neuroprotection: perspectives of epigenetic therapy for amyotrophic lateral sclerosis and schizophrenia

• Grant number: 15/02041-1
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: April 01, 2016
• End date: February 28, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Tatiana Rosado Rosenstock
• Grantee: Tatiana Rosado Rosenstock
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Clélia Rejane Antõnio ; Cristoforo Scavone ; Isaias Glezer
• Associated research grant(s): 18/08399-3 - Age-related mitochondrial metabolism and its relationship with neurogenesis in an animal model of schizophrenia, AP.R SPRINT
• Associated scholarship(s): 21/03021-5 - The role of the mitochondrial function on synaptic dynamics and neurogenesis in cells exposed to rotenone: relevance for psychiatric disorders, BP.DR; 19/17725-4 - The role of mitochondrial degradation to cellular homeostasis: a study in patients stem cells (iPSC) with familial Amyotrophic Lateral Sclerosis, BP.IC; 18/09084-6 - Functional studies in lymphocytes from Amyotrophic Lateral Sclerosis patients: relevance to biomarkers determination, BP.IC; 17/02295-9 - Mitochondrial dynamics and degradation in schizophrenia models, BP.IC; 16/12039-7 - Lysine(K)-deacetylases modulation and its role in mitochondrial metabolism, dynamics and degradation: possible neuroprotection for amyotrophic lateral sclerosis, BP.MS

Abstract

Because lysine(K)-deacetylases (KDACs) regulate proteins involved in mechanisms such as gene transcription, cellular clearance and metabolism, in which mitochondria plays an essential role, the aim of this project is to characterize the role of KDACs on mitochondrial function and degradation (mitophagy) in different models of Amyotrophic Lateral Sclerosis (ALS) and Schizophrenia (SHZ); it is known that mitochondria is related to the etiology and/or progression of these disorders. In addition, it is described that KDACs being the main responsible for epigenetic modification, it becomes the major key between molecular events and behavioral alterations; therefore, it will be also evaluated the role of KDACs as neuroprotective agents. To reach the goals proposed herein, neurons and astrocytes from hSOD1 G93A and SHR rats and immortalized cells in the presence or absence of mutant SOD1 and DISC-1 will be treated with different KDACs modulators and/or will be transfected with plasmids, si- or shRNAs against specifics KDACs. Thus, it is expected that this project discloses the neuroprotection role of KDAC in the two major brain cellular types and, as a consequence, new therapeutic tools could be developed. Hence, epigenetic modifications against mitochondrial dysfunction may possibly be the target of future projects (GraphAbstract - ATTACHMENT I). (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)

GRISOLIA, BEATRIZ; BRITO, MARIANA; ROSENSTOCK, TATIANA. Mitochondrial function, biogenesis and dynamics deregulation in ALS patients PBMCs: a potential biomarker to enable a reliable prognosis. EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, v. 49, p. 1-pg., 2019-04-01. (15/02041-1)

ZATYKA, MALGORZATA; ROSENSTOCK, TATIANA R.; SUN, CONGXIN; PALHEGYI, ADINA M.; HUGHES, GEORGINA W.; LARA-REYNA, SAMUEL; ASTUTI, DEWI; DI MAIO, ALESSANDRO; SCIAUVAUD, AXEL; KORSGEN, MIRIAM E.; et al. Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome. STEM CELL REPORTS, v. 18, n. 5, p. 17-pg., 2023-05-09. (15/02041-1)

SILVA, LUIZ FELIPE SOUZA E; SIENA, AMANDA; YUZAWA, JESSICA MAYUMI; DE BARROS TORRESI, JORGE LUIZ; ZIROLDO, ALAN; ROSENSTOCK, TATIANA ROSADO. Sirtuins Modulators Counteract Mitochondrial Dysfunction in Cellular Models of Hypoxia: Relevance to Schizophrenia. Neuroscience, v. 524, p. 16-pg., 2023-06-26. (15/02041-1, 15/25595-2, 18/13814-0, 19/17725-4)

SIENA, AMANDA; YUZAWA, JESSICA MAYUMI CAMARGO; RAMOS, ALINE CAMARGO; HENRIQUE, ELISANDRA; BRITO, MARIANA DUTRA; CALVAZARA, MARIANA BENDLIN; ROSENSTOCK, TATIANA ROSADO. Neonatal Rotenone Administration Induces Psychiatric Disorder-Like Behavior and Changes in Mitochondrial Biogenesis and Synaptic Proteins in Adulthood. Molecular Neurobiology, v. 58, n. 7, p. 3015-3030, JUL 2021. (16/12039-7, 15/02041-1)

VARGA, THIAGO GARCIA; DE TOLEDO SIMOES, JUAN GUILHERME; SIENA, AMANDA; HENRIQUE, ELISANDRA; DA SILVA, REGINA CLAUDIA BARBOSA; DOS SANTOS BIONI, VINICIUS; RAMOS, ALINE CAMARGO; ROSENSTOCK, TATIANA ROSADO. Haloperidol rescues the schizophrenia-like phenotype in adulthood after rotenone administration in neonatal rats. Psychopharmacology, JUN 2021. (15/02041-1, 15/26820-0, 19/17725-4)

ARAUJO, BEATRIZ GRISOLIA; SOUZA E SILVA, LUIZ FELIPE; TORRESI, JORGE LUIZ DE BARROS; SIENA, AMANDA; VALERIO, BERENICE CATALDO OLIVEIRA; BRITO, MARIANA DUTRA; ROSENSTOCK, TATIANA ROSADO. Decreased Mitochondrial Function, Biogenesis, and Degradation in Peripheral Blood Mononuclear Cells from Amyotrophic Lateral Sclerosis Patients as a Potential Tool for Biomarker Research. Molecular Neurobiology, AUG 2020. (15/02041-1, 18/09084-6, 15/25595-2, 16/12039-7)

BRITO, MARIANA DUTRA; GOMES DA SILVA, GUSTAVO FERRO; TILIERI, ERICK MUTTI; ARAUJO, BEATRIZ GRISOLIA; CALIO, MICHELE LONGONI; ROSENSTOCK, TATIANA ROSADO. Metabolic Alteration and Amyotrophic Lateral Sclerosis Outcome: A Systematic Review. FRONTIERS IN NEUROLOGY, v. 10, NOV 20 2019. (15/02041-1, 16/12039-7, 18/09084-6)

SOUZA E SILVA, LUIZ FELIPE; BRITO, MARIANA DUTRA; CAMARGO YUZAWA, JESSICA MAYUMI; ROSENSTOCK, TATIANA ROSADO. Mitochondrial Dysfunction and Changes in High-Energy Compounds in Different Cellular Models Associated to Hypoxia: Implication to Schizophrenia. SCIENTIFIC REPORTS, v. 9, DEC 2 2019. (15/02041-1, 16/12039-7, 15/25595-2)

CALIO, MICHELE LONGONI; HENRIQUES, ELISANDRA; SIENA, AMANDA; BERTONCINI, CLELIA REJANE ANTONIO; GIL-MOHAPEL, JOANA; ROSENSTOCK, TATIANA ROSADO. Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment. FRONTIERS IN NEUROSCIENCE, v. 14, JUL 15 2020. (15/02041-1)

VARGA, THIAGO GARCIA; DE TOLEDO SIMOES, JUAN GUILHERME; SIENA, AMANDA; HENRIQUE, ELISANDRA; DA SILVA, REGINA CLAUDIA BARBOSA; DOS SANTOS BIONI, VINICIUS; RAMOS, ALINE CAMARGO; ROSENSTOCK, TATIANA ROSADO. Haloperidol rescues the schizophrenia-like phenotype in adulthood after rotenone administration in neonatal rats. Psychopharmacology, v. 238, n. 9, p. 2569-2585, SEP 2021. (19/17725-4, 15/02041-1, 15/26820-0)

SUN, CONGXIN; SERANOVA, ELENA; COHEN, MALKIEL A.; CHIPARA, MIRUNA; ROBERTS, JENNIE; ASTUTI, DEWI; PALHEGYI, ADINA M.; ACHARJEE, ANIMESH; SEDLACKOVA, LUCIA; KATAURA, TETSUSHI; et al. NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency. CELL REPORTS, v. 42, n. 5, p. 27-pg., 2023-05-30. (15/02041-1)

ARAUJO, BEATRIZ GRISOLIA; SOUZA E SILVA, LUIZ FELIPE; TORRESI, JORGE LUIZ DE BARROS; SIENA, AMANDA; VALERIO, BERENICE CATALDO OLIVEIRA; BRITO, MARIANA DUTRA; ROSENSTOCK, TATIANA ROSADO. Decreased Mitochondrial Function, Biogenesis, and Degradation in Peripheral Blood Mononuclear Cells from Amyotrophic Lateral Sclerosis Patients as a Potential Tool for Biomarker Research. Molecular Neurobiology, v. 57, n. 12, p. 19-pg., 2020-08-25. (15/02041-1, 16/12039-7, 15/25595-2, 18/09084-6)

SIENA, AMANDA; YUZAWA, JESSICA MAYUMI; RAMOS, ALINE CAMARGO; HENRIQUE, ELISANDRA; DE SOUZA E SILVA, LUIZ FELIPE; BRITTO, MARIANA; ROSENSTOCK, TATIANA ROSADO. Neonatal Rotenone administration induces mitochondria metabolism and biogenesis deregulation leading to synaptic dynamics and behavioral alterations mimicking neurodevelopmental disorder. EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, v. 49, p. 2-pg., 2019-04-01. (15/02041-1)

SOUZA SILVA, LUIZ FELIPE; ROSENSTOCK, TATIANA ROSADO; CAMARGO YUZAWA, JESSICA MAYUMI. Hypoxia-induced mitochondrial metabolism deregulation associated to schizophrenia. EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, v. 49, p. 2-pg., 2019-04-01. (15/02041-1)