The role of mitochondrial degradation to cellular homeostasis: a study in patients stem cells (iPSC) with familial Amyotrophic Lateral Sclerosis

• Grant number: 19/17725-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2020
• End date: July 31, 2020
• Field of knowledge: Interdisciplinary Subjects
• Principal Investigator: Tatiana Rosado Rosenstock
• Grantee: Thiago Garcia Varga
• Host Institution: Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP). Fundação Arnaldo Vieira de Carvalho. São Paulo , SP, Brazil
• Associated research grant: 15/02041-1 - The role of lysine(K)-deacetylases on mitochondrial disorders's neuroprotection: perspectives of epigenetic therapy for amyotrophic lateral sclerosis and schizophrenia, AP.JP

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease, characterized by motor neuron death in the brain and the spinal cord. ALS manifests as sporadic (sALS) in most cases (around 90%) or familial (fALS) in around 10% of occurrences, which are related to genetic causes. Previous studies have already related ALS to a variety of factors such as inflammation, excitotoxicity, inclusion of ubiquitinated proteins, autophagy and more specifically mitophagy which has been increasingly more related to the pathogenesis of the disease. On account of that, the objective of our project is to study the relation between autophagy, mitochondrial degradation and cellular survival in a relevant human model for clinical trials composed of induced pluripotent stem cells (IPSCs) of patients with fALS that present the most common mutations such as the ones in SOD1 and C9ORF72. Besides that, we will use modulators of mitochondrial degradation in order to find a possible neuroprotective effect in one or more mutations since there are few therapeutic options that are not very effective to treat the disease. This project is, thusly, relevant not only to better understand how the main mutations related to fALS affect mitochondrial degradation and cellular viability, but also to determine common pathways to the pathogenesis and progression of ALS in the different cell types. Hence, our proposal is extremely relevant to the development of new therapeutic strategies that could inhibit the progression of the disease and promote neuroprotection.

Scientific publications

(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)

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)

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)

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)