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Published on: February 8, 2019
Ethylmalonic acid modulates Na+, K(+)-ATPase activity and mRNA levels in rat cerebral cortex
Patrícia Fernanda Schuck1, Dênis Reis De Assis, Carolina Maso Viegas
1Laboratório de Erros Inatos do Metabolismo, Programa de Pós-graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil. patricia.schuck@pq.cnpq.br
Abstract:
Ethylmalonic acid (EMA) accumulates in tissues of patients affected by short-chain acyl-CoA dehydrogenase deficiency and ethylmalonic encephalopathy, illnesses characterized by variable neurological symptoms. In this work, we investigated the in vitro and in vivo EMA effects on Na(+), K(+)-ATPase (NAK) activity and mRNA levels in cerebral cortex from 30-day-old rats. For in vitro studies, cerebral cortex homogenates were incubated in the presence of EMA at 0.5, 1, or 2.5 mM concentrations for 1 h. For in vivo experiments, animals received three subcutaneous EMA injections (6 μmol g(-1); 90-min interval) and were killed 60 min after the last injection. After that, NAK activity and its mRNA expression were measured. We observed that EMA did not affect this enzyme activity in vitro. In contrast, EMA administration significantly increased NAK activity and decreased mRNA NAK expression as assessed by semiquantitative reverse transcriptase polymerase chain reaction when compared with control group. Considering the high score of residues prone to phosphorylation on NAK, this profile can be associated with a possible regulation by specific phosphorylation sites of the enzyme. Altogether, the present results suggest that NAK alterations may be involved in the pathophysiology of brain damage found in patients in which EMA accumulates.
Insights
Ethylmalonic acid (EMA) accumulation in brain tissue may impact neurological function. Studies show EMA increases Na(+), K(+)-ATPase activity while decreasing its mRNA levels in rat brains, suggesting a role in neurological disease.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Ethylmalonic acid (EMA) is implicated in neurological disorders like short-chain acyl-CoA dehydrogenase deficiency and ethylmalonic encephalopathy.
- These conditions present with diverse neurological symptoms, suggesting a link between EMA accumulation and brain dysfunction.
Purpose of the Study:
- To investigate the effects of EMA on Na(+), K(+)-ATPase (NAK) activity and mRNA expression in the rat cerebral cortex.
- To explore the potential role of NAK alterations in the pathophysiology of EMA-related neurological damage.
Main Methods:
- In vitro incubation of rat cerebral cortex homogenates with varying EMA concentrations (0.5–2.5 mM).
- In vivo administration of EMA to rats via subcutaneous injections, followed by NAK activity and mRNA expression analysis.
- Quantitative assessment using semiquantitative reverse transcriptase polymerase chain reaction for NAK mRNA levels.
Main Results:
- In vitro studies showed no significant effect of EMA on NAK activity.
- In vivo EMA administration led to a significant increase in NAK activity in the rat cerebral cortex.
- EMA treatment in vivo resulted in a significant decrease in NAK mRNA expression.
Conclusions:
- EMA affects NAK activity and expression in vivo, but not in vitro, suggesting complex regulatory mechanisms.
- The observed alterations in NAK (increased activity, decreased mRNA) may be linked to phosphorylation events.
- NAK dysregulation is a potential contributing factor to the brain damage observed in conditions with EMA accumulation.
