Cerebral Energy Metabolism in Phenylketonuria: Findings by Quantitative In Vivo 31P MR Spectroscopy

Pietz, Joachim; Rupp, André; Ebinger, Friedrich; Rating, D.; Mayatepek, Ertan; Boesch, Chris; Kreis, Roland

doi:10.1203/01.pdr.0000055867.83310.9e

Cited by 51 publications

(41 citation statements)

References 35 publications

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“…Altered glucose metabolism has been implicated as a pathological mechanism contributing to pathophysiology in neurodegenerative disorders, including neuronal ceroid lipofuscinosis (62,63), chromosomal disorders, such as Down syndrome (64), and inborn errors of metabolism, such as phenylketonuria (65)(66)(67)(68). In the current study, we identified decreased expression of pyruvate kinase isozymes M1/M2, transaldolase, and phosphoglycerate mutase 1 in Dhcr ⌬3-5/⌬3-5 brain tissue (Table II).…”

Section: Sc5dsupporting

confidence: 57%

Quantitative Proteomics Analysis of Inborn Errors of Cholesterol Synthesis

Jiang

Backlund

Wassif

et al. 2010

Molecular & Cellular Proteomics

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Smith-Lemli-Opitz syndrome (SLOS) and lathosterolosis are malformation syndromes with cognitive deficits caused by mutations of 7-dehydrocholesterol reductase (DHCR7) and lathosterol 5-desaturase (SC5D), respectively. DHCR7 encodes the last enzyme in the Kandutsch-Russel cholesterol biosynthetic pathway, and impaired DHCR7 activity leads to a deficiency of cholesterol and an accumulation of 7-dehydrocholesterol. SC5D catalyzes the synthesis of 7-dehydrocholesterol from lathosterol. Impaired SC5D activity leads to a similar deficiency of cholesterol but an accumulation of lathosterol. Although the genetic and biochemical causes underlying both syndromes are known, the pathophysiological processes leading to the developmental defects remain unclear. To study the pathophysiological mechanisms underlying SLOS and lathosterolosis neurological symptoms, we performed quantitative proteomics analysis of SLOS and lathosterolosis mouse brain tissue and identified multiple biological pathways affected in Dhcr7 ⌬3-5/⌬3-5 and Sc5d ؊/؊ E18.5 embryos. These include alterations in mevalonate metabolism, apoptosis, glycolysis, oxidative stress, protein biosynthesis, intracellular trafficking, and cytoskeleton. Comparison of proteome alterations in both Dhcr7 ⌬3-5/⌬3-5 and Sc5d ؊/؊ brain tissues helps elucidate whether perturbed protein expression was due to decreased cholesterol or a toxic effect of sterol precursors. Validation of the proteomics results confirmed increased expression of isoprenoid and cholesterol synthetic enzymes. This alteration of isoprenoid synthesis may underlie the altered posttranslational modification of Rab7, a small GTPase that is functionally dependent on prenylation with geranylgeranyl, that we identified and validated in this study. These data suggested that although cholesterol synthesis is impaired in both Dhcr7⌬3-5/⌬3-5 and Sc5d ؊/؊ embryonic brain tissues the synthesis of nonsterol isoprenoids may be increased and thus contribute to SLOS and lathosterolosis pathology. This proteomics study has provided insight into the pathophysiological mechanisms of SLOS and lathosterolosis, and understanding these pathophysiological changes will help guide clinical therapy for SLOS and lathosterolosis.

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Section: Sc5dsupporting

confidence: 57%

Quantitative Proteomics Analysis of Inborn Errors of Cholesterol Synthesis

Jiang

Backlund

Wassif

et al. 2010

Molecular & Cellular Proteomics

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“…Rech et al (13) report a reduced activity of mitochondrial complexes I-III using a combined test system in brain homogenates from rats. Moreover, 31 P magnetic resonance spectroscopy revealed an acute effect of phenylalanine on cerebral energy metabolism (14). A subtle abnormality such as elevated ADP concentration under steadystate conditions was accentuated by phenylalanine loading of PKU patients.…”

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confidence: 96%

Phenylalanine Reduces Synaptic Density in Mixed Cortical Cultures from Mice

et al. 2006

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Classical phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase, resulting in an accumulation of its upstream metabolite phenylalanine in brain tissue and cerebrospinal fluid of PKU patients. PKU is neuropathologically characterized by reduced dendritic arborization, loss of synapses, and neurodegeneration. We investigated whether increased concentrations of phenylalanine cause reduced synaptic density and alter dendritic branching. We treated primary cortical neurons differentiated for 21 d in vitro with 5 mM phenylalanine in the presence of all essential amino acids. Immunocytochemical analysis of 12 and 21 d in vitro primary neurons revealed no changes of dendritic morphology or neuronal viability but a significant difference in synaptic density, suggesting that elevated concentrations of extracellular phenylalanine cause an impairment of synaptogenesis. Although impairment of cerebral energy metabolism has been identified as an important pathophysiological principal in many diseases, respiratory chain function has not been extensively studied in PKU before. We investigated whether phenylalanine inhibits respiratory chain complexes I-V. In vitro analysis revealed no inhibitory effect of phenylalanine on complexes I-V, but an inhibition of pyruvate kinase, a key enzyme of glycolysis, catalyzing the formation of pyruvate. Pyruvate kinase is part of the enzyme assay to investigate enzyme activity of mitochondrial complex V and it remains to be elucidated whether this finding is relevant in vivo. In conclusion, elevated concentrations of phenylalanine might be involved in mechanisms underlying impaired synaptogenesis in PKU, supporting the common therapeutic strategy to reduce phenylalanine concentrations in the brain to prevent neurodegeneration. (Pediatr Res 59: 544-548, 2006)

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“…A diminished activity of a single enzyme of the phoryltransfer network is rather well tolerated. However, a decrease in the activity of two or more enzymes of this network may compromise the brain development (Pietz et al 2003), (Rojas et al 2012). In addition, results of observational studies and trials might differ because different NSAIDs have different effects on AD (Gasparini et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Amyloid-β peptide absence in short term effects on kinase activity of energy metabolism in mice hippocampus and cerebral cortex

Ianiski

Rech

Nishihira

et al. 2016

An. Acad. Bras. Ciênc.

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Considering that Alzheimer's disease is a prevalent neurodegenerative disease worldwide, we investigated the activities of three key kinases: creatine kinase, pyruvate kinase and adenylate kinase in the hippocampus and cerebral cortex in Alzheimer's disease model. Male adult Swiss mice received amyloid-β or saline. One day after, mice were treated with blank nanocapsules (17 ml/kg) or meloxicam-loaded nanocapsules (5 mg/kg) or free meloxicam (5 mg/kg). Treatments were performed on alternating days, until the end of the experimental protocol. In the fourteenth day, kinases activities were performed. Amyloid-β did not change the kinases activity in the hippocampus and cerebral cortex of mice. However, free meloxicam decrease the creatine kinase activity in mitochondrial-rich fraction in the group induced by amyloid-β, but for the cytosolic fraction, it has raised in the activity of pyruvate kinase activity in cerebral cortex. Further, meloxicam-loaded nanocapsules administration reduced adenylate kinase activity in the hippocampus of mice injected by amyloid-β. In conclusion we observed absence in short-term effects in kinases activities of energy metabolism in mice hippocampus and cerebral cortex using amyloid-β peptide model. These findings established the foundation to further study the kinases in phosphoryltransfer network changes observed in the brains of patients post-mortem with Alzheimer's disease.

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Cerebral Energy Metabolism in Phenylketonuria: Findings by Quantitative In Vivo 31P MR Spectroscopy

Cited by 51 publications

References 35 publications

Quantitative Proteomics Analysis of Inborn Errors of Cholesterol Synthesis

Quantitative Proteomics Analysis of Inborn Errors of Cholesterol Synthesis

Phenylalanine Reduces Synaptic Density in Mixed Cortical Cultures from Mice

Amyloid-β peptide absence in short term effects on kinase activity of energy metabolism in mice hippocampus and cerebral cortex

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