Morphologic and histoanatomic observations of the brain in untreated human phenylketonuria

Bauman, Margaret L.; Kemper, T

doi:10.1007/bf00692698

Cited by 131 publications

(77 citation statements)

References 29 publications

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“…The L- [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]leucine method is based on a compartmental model for the behavior of leucine in brain that includes bidirectional carrier-mediated transport of leucine at the bloodbrain barrier, an extracellular and multiple intracellular compartments in brain, and the possibility that unlabeled leucine from the breakdown of tissue protein can be reincorporated into tissue protein. The application of the model together with an appropriate experimental design, i.e., a pulse injection of a tracer dose of L-[1-14 C]leucine followed by a 60-min interval for clearance of the tracer from the blood and the brain, gives rise to Eq.…”

Section: Discussionmentioning

confidence: 99%

“…The radiolabeled tracer is [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]leucine, which is used in conjunction with quantitative autoradiography to achieve spatial localization of the labeled protein in the brain for the determination of rates of protein synthesis in discrete brain regions (17). The operational equation of the method is:…”

Section: Methodsmentioning

confidence: 99%

“…It is only by inference that cerebral protein synthesis rates appear to be affected. Untreated patients with PKU have lower brain weights (6), changes in myelin structure (7), and reductions in dendritic arborization and numbers of synaptic spines (6). Selectively vulnerable regions of the brain are those that undergo development postnatally.…”

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confidence: 99%

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Cerebral protein synthesis in a genetic mouse model of phenylketonuria

Smith

Kang²

2000

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Cerebral protein synthesis in a genetic mouse model of phenylketonuria

Smith

Kang²

2000

Proc. Natl. Acad. Sci. U.S.A.

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“…Histopathological investigations of untreated PKU patients revealed severe impairment of brain architecture and maturation, with abnormalities in myelination, cell density and cell organization. Dendritic arborization was altered and the number of synaptic spines was decreased (9). A more recent autopsy study of an untreated patient reports neuronal loss reduced size of neurons and decreased dendritic processes of Purkinje cells (10).…”

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confidence: 98%

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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“…Phenylalanine interferes with brain development and results in severe MR, microcephaly, epilepsy, and behavioral problems. These symptoms appear to be the direct consequence of neuronal cell loss, white matter abnormalities, dendritic simplification, and synaptic density reduction (1)(2)(3)(4)(5). Previous studies demonstrated that phenylalanine reduced Naϩ, Kϩ-ATPase and creatine kinase activity in rat brain (6 -8).…”

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confidence: 99%

Differential Effects of Phenylalanine on Rac1, Cdc42, and RhoA Expression and Activity in Cultured Cortical Neurons

Zhang

Yuan

et al. 2007

Pediatr Res

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Phenylketonuria (PKU) is characterized by a high concentration of phenylalanine, which can lead to mental retardation. One of the characteristic pathologic changes in untreated phenylketonuria patients is a reduction in the number of axons, dendrites, and synapses in the brain. This is thought to be due to the toxic effects of phenylalanine and/or its metabolites, however, the underlying mechanism remains unclear. In this study, we observed that phenylalanine reduced the number of dendrites and dendritic spines in cultured neurons. We further demonstrated that phenylalanine down-regulated Rac1, Cdc42, and RhoA mRNA and protein expression. Pull-down assays indicated that phenylalanine caused a decrease in Rac1/Cdc42 activity but increased RhoA activity. Expression of a dominant negative RhoA or treatment with a Rho-associated kinase specific inhibitor, Y-27632, partly inhibited the phenylalanine-induced decrease in dendrite numbers. In conclusion, we have demonstrated that phenylalanine affects the expression and activity of Rac1, Cdc42, and RhoA. Furthermore, RhoA signaling is involved in the inhibitory effect of phenylalanine on dendritic branching. These results may provide an important insight into the molecular mechanism underlying phenylalanine-induced abnormalities of dendrites, specifically in phenylketonuria neuronal injury. (Pediatr Res 62: 8-13, 2007) P henylketonuria (PKU) is one of the most frequent inborn disorders of amino acid metabolism. It is caused by a deficiency in phenylalanine hydroxylase (PAH), resulting in an accumulation of its upstream metabolite phenylalanine, mainly in brain tissue and the cerebrospinal fluid of PKU patients. Phenylalanine interferes with brain development and results in severe MR, microcephaly, epilepsy, and behavioral problems. These symptoms appear to be the direct consequence of neuronal cell loss, white matter abnormalities, dendritic simplification, and synaptic density reduction (1-5). Previous studies demonstrated that phenylalanine reduced Naϩ, Kϩ-ATPase and creatine kinase activity in rat brain (6 -8). Moreover, some neurotransmitters such as serotonin and dopamine were deficient in PKU animal models (9). Glushakov et al. (10) found that a high concentration of phenylalanine attenuated NMDA-activated currents in cultured hippocampal neurons. In vivo 31 P-MRS demonstrated abnormalities of cerebral energy metabolism in PKU, indicating a link between phenylalanine neurotoxicity and imbalances of cerebral energy metabolism (11). Lately, Horster et al. (5) revealed that phenylalanine reduced synaptic density and simultaneously inhibited pyruvate kinase in mixed cortical cultures. Our laboratory reported that phenylalanine and its metabolites caused neuronal cell apoptosis in vitro (12,13). Although these observations demonstrate that phenylalanine is probably the main causative agent of brain injury in PKU, the pathophysiological mechanisms of its actions in brain injury are multiple and not fully understood.As dendrites are the site of most synaptic c...

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Morphologic and histoanatomic observations of the brain in untreated human phenylketonuria

Cited by 131 publications

References 29 publications

Cerebral protein synthesis in a genetic mouse model of phenylketonuria

Cerebral protein synthesis in a genetic mouse model of phenylketonuria

Phenylalanine Reduces Synaptic Density in Mixed Cortical Cultures from Mice

Differential Effects of Phenylalanine on Rac1, Cdc42, and RhoA Expression and Activity in Cultured Cortical Neurons

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