Direct conversion of fibroblasts from patients in induced neurons as a tool to elucidate the pathophysiology of neurological alterations and design of therapeutic strategies for methylmalonic acidemia

• Grant number: 23/00097-6
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2023
• End date: September 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: César Augusto João Ribeiro
• Grantee: César Augusto João Ribeiro
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil
• Associated researchers: Al-Walid Mohsen-Mohammed ; Fernando Augusto de Oliveira Ribeiro
• Associated scholarship(s): 25/03726-0 - Direct conversion of fibroblasts from patients in induced neurons as a tool to elucidate the pathophysiology of neurological alterations and design of therapeutic strategies for methylmalonic acidemia, BP.TT

Abstract

Organic acidemias are inherited diseases relatively common in hospitalized children, with a prevalence of 1: 1,000 newborns. Affected patients accumulate specific organic acids in their tissues and biological fluids and have severe dysfunction mainly in organs highly dependent of energy such as brain and heart. Without proper treatment, a large number of these patients have fatal outcome in the first year of life, while those who survive the early stages have a varying degree of sequels. Methylalonic acidemia is a disorder of propionyl-CoA pathway, caused by deficiency in the activity of L-methylmalonyl-CoA mutase or in its coenzyme adenosylcobalamin. This disease is clinical and biochemical characteristics of this disease are, respectively, neurological alterations and metabolic acidosis and accumulation of methylmalonic, 3-hydroxypropionic and methylcitric acids. Considering that the pathogenesis of brain damage this disease is poorly understood, the goal of this project is to investigate the mechanisms involved in the neurological alterations observed in patients with methylmalonic acidemia in a cellular model of induced neurons, obtained through cellular reprogramming of fibroblasts from affected patients through their exposure to a defined cocktail of inhibitors and activators of specific signaling pathways. Morphology and expression of specific neuronal markers (Tuj1, MAP2 and NeuN) will be evaluated, as well as neuronal functionality by electrophysiology. Neuroprotective capacities of anaplerotic and antioxidant compounds will also be evaluated in this cellular model. It is expected that a cellular model obtained directly from affected patients may contribute to the understanding of the cellular and molecular bases in this pathology, as well as to characterizing possible therapeutic targets, allowing the proposition of protection strategies based on the pathogenic mechanisms of cellular degeneration in this disease. (AU)