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Investigation of the effects of isovaleric acid associated with hyperammonemia on energy metabolism in neural cell lines: implications for isovaleric acidemia

Grant number: 19/12005-3
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): August 01, 2019
Effective date (End): July 31, 2020
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:César Augusto João Ribeiro
Grantee:Marcella Bacelar dos Santos
Home Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil


Isovaleric acidemia is an inborn metabolic disorder of leucine catabolism, characterized by accumulation of isovaleric acid (IVA) in tissue and body fluids of affected patients. These patients present seizures, mental retardation and other severe neurologic symptoms, as well as acute central nervous system degeneration. Biochemically, patients present metabolic acidosis with mild ketonuria, lactic acidemia and marked hyperammonemia. The neurological symptoms worsen suddenly during and after metabolic decompensation elicited by systemic infections or vaccination, leading to acute brain degeneration in a significant number of patients. In this context, few studies have been carried out to understand the etiopathogenesis of the neurological dysfuncion and brain damage presented by these patients during catabolic stress. Thus, the objective of the present project is to investigate in neuronal cell lines (human neuroblastomes SH-SY5Y) the mechanisms of toxicity involved in isovaleric acidemia during catabolic stress situations, using an in vitro model of hyperammonemia, in order to mimic the patient's condition during catabolic decompensation (characterized by rise of ammonia levels in plasma and tissues). We aim to contribute to the understanding of cellular and molecular basis of this disease, as well as characterize possible targets to neuroprotective therapeutic strategies based on the elucidation of the pathogenic degenerative mechanisms in isovaleric acidemia.