Chronic postnatal administration of methylmalonic acid provokes a decrease of myelin content and ganglioside N-acetylneuraminic acid concentration in cerebrum of young rats

Brusque, Ana Maria; Rotta, Liane Nanci; Pettenuzzo, Letícia Ferreira; Junqueira, Débora; Schwarzbold, Carolina Vargas; Wyse, Angela T. S.; Wannmacher, Clóvis Milton Duval; Dutra-Filho, Carlos Severo; Wajner, Moaçir

doi:10.1590/s0100-879x2001000200010

Cited by 12 publications

(6 citation statements)

References 18 publications

(13 reference statements)

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“…Lipid metabolism involves SMPD4/NSMA3 and SUMF2, which belong to the glycosphingolipidic metabolism; SMPD4/NSMA3 is over-represented in the cells not-expressing MUT; it could be a protein of relevant interest, because it catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide. A significant myelin content reduction was observed in the cerebrum from rat brains after the administration of MMA [ 31 ]. The MMA content may be related to the delayed myelination/cerebral atrophy and neurological dysfunction found in methylmalonic acidemia children.…”

Section: Resultsmentioning

confidence: 99%

Label-Free Quantitative Proteomics in a Methylmalonyl-CoA Mutase-Silenced Neuroblastoma Cell Line

Costanzo

Cevenini

Marchese

et al. 2018

IJMS

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Methylmalonic acidemias (MMAs) are inborn errors of metabolism due to the deficient activity of methylmalonyl-CoA mutase (MUT). MUT catalyzes the formation of succinyl-CoA from methylmalonyl-CoA, produced from propionyl-CoA catabolism and derived from odd chain fatty acids β-oxidation, cholesterol, and branched-chain amino acids degradation. Increased methylmalonyl-CoA levels allow for the presymptomatic diagnosis of the disease, even though no approved therapies exist. MMA patients show hyperammonemia, ketoacidosis, lethargy, respiratory distress, cognitive impairment, and hepatomegaly. The long-term consequences concern neurologic damage and terminal kidney failure, with little chance of survival. The cellular pathways affected by MUT deficiency were investigated using a quantitative proteomics approach on a cellular model of MUT knockdown. Currently, a consistent reduction of the MUT protein expression was obtained in the neuroblastoma cell line (SH-SY5Y) by using small-interfering RNA (siRNA) directed against an MUT transcript (MUT siRNA). The MUT absence did not affect the cell viability and apoptotic process in SH-SY5Y. In the present study, we evaluate and quantify the alterations in the protein expression profile as a consequence of MUT-silencing by a mass spectrometry-based label-free quantitative analysis, using two different quantitative strategies. Both quantitative methods allowed us to observe that the expression of the proteins involved in mitochondrial oxido-reductive homeostasis balance was affected by MUT deficiency. The alterated functional mitochondrial activity was observed in siRNA_MUT cells cultured with a propionate-supplemented medium. Finally, alterations in the levels of proteins involved in the metabolic pathways, like carbohydrate metabolism and lipid metabolism, were found.

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Section: Resultsmentioning

confidence: 99%

Label-Free Quantitative Proteomics in a Methylmalonyl-CoA Mutase-Silenced Neuroblastoma Cell Line

Costanzo

Cevenini

Marchese

et al. 2018

IJMS

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“…The accumulation of MMA is known to cause dysfunction in neuronal development which has been related to the clinical symptoms in patients. 5,29 Because there is a lack of investigations about the molecular mechanisms involved in the alterations in neuronal differentiation of immature and mature neurons, in this study, we examined the toxic effects of MMA on undifferentiated and differentiated SH-SY5Y cells in a range of concentrations similar to those observed in affected patients. 8,10 Moreover, it was demonstrated that exposition of both primary and lineage neural cells to MMA leads to intracellular accumulation of this metabolite in a time-dependent way.…”

Section: T H Imentioning

confidence: 99%

“…Neurologic dysfunctions in methylmalonic acidemia are important clinical manifestations in patients. Previous studies suggested that primary or secondary mitochondrial dysfunction is potentially elicited by MMA, proposing that they are related to the neurological alterations observed in patients. − Moreover, it has been argued that other metabolites derived from the accumulation of MMA may also be the factors responsible for dysfunction in mitochondrial activity. , …”

Section: Introductionmentioning

confidence: 99%

Methylmalonic Acid Compromises Respiration and Reduces the Expression of Differentiation Markers of SH-SY5Y Human Neuroblastoma Cells

Costa

Santos

Silva

et al. 2021

ACS Chem. Neurosci.

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Methylmalonic acidemia is a rare metabolic disorder caused by the deficient activity of L-methylmalonyl-CoA mutase or its cofactor 5-deoxyadenosylcobalamin and is characterized by accumulation of methylmalonic acid (MMA) and alternative metabolites. The brain is one of the most affected tissues and neurologic symptoms, characterized by seizures, mental retardation, psychomotor abnormalities, and coma, commonly appear in newborns. The molecular mechanisms of neuropathogenesis in methylmalonic acidemia are still poorly understood, specifically regarding the impairments in neuronal development, maturation, and differentiation. In this study, we investigated the effects of MMA in both undifferentiated and differentiated phenotypes of SH-SY5Y human neuroblastoma cells. We observed an increase in glucose consumption and reduction in respiratory parameters of both undifferentiated and differentiated cells after exposition to MMA, suggesting that differentiated cells are slightly more prone to perturbations in respiratory parameters by MMA than undifferentiated cells. Next, we performed qPCR of mature neuronal-specific gene markers and measured mitochondrial functioning to evaluate the role of MMA during differentiation. Our results showed that MMA impairs the respiratory parameters only at the late stage of differentiation and downregulates the transcriptional gene profile of mature neuronal markers neuron-specific enolase (ENO2) and synaptophysin (SYP). Altogether, our findings point out important changes observed during neuronal maturation and energetic stress vulnerability that can play a role in the neurological clinical symptoms at the newborn period and reveal important molecular mechanisms that could help the screening of targets to new approaches in the therapies of this disease.

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“…The accumulation of MMA is known to cause dysfunction in neuronal development which has been related to the clinical symptoms in patients [6,23]. However, there is a lack of investigations about the molecular mechanisms involved in the alterations in neuronal differentiation of immature and mature neurons.…”

Section: Ra-differentiation Process In Sh-sy5y Cellsmentioning

confidence: 99%

Methylmalonic acid compromises mitochondrial respiration and reduces the expression of markers of differentiation in SH-SY5Y human neuroblastoma cells

Costa

Santos

Silva

et al. 2020

Preprint

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Methylmalonic acidemia is a rare metabolic disorder characterized by the accumulation of methylmalonic acid (MMA) and alternatives metabolites which is caused by the deficient activity of L-methylmalonyl-CoA mutase or its cofactor 5-deoxyadenosylcobalamin (AdoCbl). The brain is one of the affected tissues by the accumulation of this metabolite in patients. The neurologic symptoms commonly appear in newborns and are clinically characterized by seizures, mental retardation, psychomotor abnormalities, and coma. The molecular mechanisms of neuropathogenesis in methylmalonic acidemia are still poorly understood, specifically regarding the impairments in neuronal development and maturation. In this study, we firstly investigated the neurotoxicity of MMA in both undifferentiated and 7-day RA-differentiated phenotypes of SH-SY5Y human neuroblastoma cells and found alterations in energetic homeostasis after the exposition to MMA. We observed an increase in glucose consumption and reduced respiratory parameters of both undifferentiated and differentiated SH-SY5Y cells after 48 hours of exposition to MMA. RA-differentiated cells slightly indicated to be more prone to perturbations in respiratory parameters by MMA than undifferentiated cells. In order to understand whether the presence of MMA during neuronal maturation could compromise this process in neuronal cells, we performed high-resolution respirometry to evaluate the mitochondria function and qPCR assay to evaluate mRNA levels of mature neuronal-specific genes in early-stage (day 3), and late-stage (day 7) of differentiation in cells co-treated with MMA 1mM during RA mediated differentiation. Our results showed that MMA compromises the respiratory parameters of routine, ATP-linked, and maximal respiration only at the late stage of differentiation as well as downregulates the transcriptional gene profile of mature neuronal markers ENO2 and SYP. Altogether, our finds point to important alterations observed during neuronal maturation and energetic stress vulnerability that can play a role in the neurological clinical symptoms at the newborn period and reveal important molecular mechanisms that could help the screening of targets to new approaches in the therapies of this disease.

show abstract

Chronic postnatal administration of methylmalonic acid provokes a decrease of myelin content and ganglioside N-acetylneuraminic acid concentration in cerebrum of young rats

Cited by 12 publications

References 18 publications

Label-Free Quantitative Proteomics in a Methylmalonyl-CoA Mutase-Silenced Neuroblastoma Cell Line

Label-Free Quantitative Proteomics in a Methylmalonyl-CoA Mutase-Silenced Neuroblastoma Cell Line

Methylmalonic Acid Compromises Respiration and Reduces the Expression of Differentiation Markers of SH-SY5Y Human Neuroblastoma Cells

Methylmalonic acid compromises mitochondrial respiration and reduces the expression of markers of differentiation in SH-SY5Y human neuroblastoma cells

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