Relationship between myelin production and dopamine synthesis in the PKU mouse brain

Abstract

Phenylketonuria is caused by specific mutations in the phenylalanine hydroxylase gene and is characterized by elevated blood phenylalanine levels, hypomyelination in forebrain structures, reduced dopamine levels, and cognitive difficulties. To determine whether brain tyrosine levels and/or myelination play a role in the up-regulation of dopamine, phenylketonuric mice were placed on a low phenylalanine diet for 4 weeks and as blood phenylalanine levels dropped to normal, the relationships between phenylalanine, tyrosine, dopamine, myelin proteins, and axonal proteins in frontal cortex and striatum were determined using gas chromatography mass spectrometry, histology, and western blotting techniques. Blood phenylalanine rapidly decreased from an eight-fold elevation to near control levels, and blood tyrosine gradually rose from about 50% to near normal values. In frontal cortex and striatum, phenylalanine levels dropped to 2-and 1.5-fold elevations above control, respectively, and tyrosine levels increased but remained less than 70% of control in both structures. In frontal cortex, increases in dopamine and myelin basic protein occurred in a similar biphasic pattern, reaching near normal levels by week 4. In striatum, dopamine and MBP dramatically increased to near normal levels in the first week. Myelination was confirmed histologically and by western blot quantification of phosphorylated neurofilaments. In summary, our results showed: (i) an increase in dopamine despite low brain tyrosine levels and (ii) similar recovery patterns for myelination and dopamine. Since myelin/axonal interactions trigger signaling pathways that result in axonal maturation, we speculate that this interaction also may trigger signals that up-regulate neurotransmitter synthesis. Keywords: axon, blood-brain barrier, dopamine, myelin, phenylketonuria, tyrosine. In the CNS, oligodendrocytes extend numerous processes, and from the distal tip of each process, a membrane sheet is assembled and wrapped around a segment of axon as an internode of myelin. Myelin is a highly metabolically active membrane that, under normal conditions, remains connected to and is supported by the oligodendrocyte cell body for the life span of the oligodendrocyte. Myelin is essential for the rapid conduction of action potentials and, therefore, there may be devastating consequences if oligodendrocytes fail to produce myelin (hypomyelination) or lose their myelin (demyelination) as a consequence of disease.One disease in which hypomyelination occurs in specific forebrain tracts, but neurons and their axons are spared, is the autosomal recessive disorder phenylketonuria (PKU) (Malamud 1966;Dyer et al. 1996). PKU is caused by a rise in blood phenylalanine (Phe) levels, due to a deficiency in the enzyme phenylalanine hydroxylase (PAH) (Jervis 1953). PAH is expressed primarily in liver and not in brain, and catalyzes the conversion of Phe to tyrosine (Hsieh and Berry 1979). Blood Phe levels normally are about 121 lM; however, in untreated individuals (and mice) ...

Pathologic and Immunohistochemical Findings in Hypothalamic and Mesencephalic Regions in the Pahenu2 Mouse Model for Phenylketonuria

“…In the prefrontal cortex, nucleus accumbens, and caudate putamen, there was also a marked reduction of DA release. Joseph and Dyer (9) showed that by placing the PKU mice on a low-Phe diet, DA and myelin basic protein were increased to near-normal levels in the striatum and frontal cortex, indicating a positive relationship between myelination and DA production.…”

“…These results concur with our observations that there were no detectable histologic changes in these specific regions, although we did identify morphologic and immunohistochemical changes in the hypothalamus and mesencephalon. In addition, Joseph and Dyer (9) reported that when they used Luxol fast blue, a myelin-specific stain, there clearly was an increase in the amount of myelin in subcortical white matter, corpus callosum, and striatum of treated PKU mice compared with respective structures in untreated PKU mouse brain.…”

Nouvelles approches thérapeutiques de la phénylcétonurie

“…Enfin, les dommages cérébraux peuvent aussi être causés par les anomalies de myélinisation et de démyélinisation. Ces anomalies sont apparemment le résultat de la combinaison d'une augmentation du turnover de la myéline et d'une réduction de sa production, qui sont des effets secondaires de l'augmentation de la Phe dans le cerveau [6,7] .…”

Nuevos enfoques del tratamiento de la fenilcetonuria

“…Otro importante mecanismo del daño cerebral en la FCU se atribuye a anomalías de la mielinización y la desmielinización. Estas anomalías son, por lo visto, el resultado de una combinación del incremento del recambio de mielina y la disminución de la producción de mielina, que son respuestas secundarias a un aumento de la phe cerebral [6,7] .…”