Is there a relationship between 3-hydroxy-3-methylglutaryl coenzyme a reductase activity and forebrain pathology in the PKU mouse?

Abstract

Previous reports have suggested that elevated levels of phenylalanine inhibit cholesterol synthesis. The goals of this study were to investigate if perturbations in cholesterol synthesis exist in the PAHenu2 genetic mouse model for phenylketonuria (PKU), and if so, initiate studies determining if they might underlie the white matter pathology that exists in PKU forebrain. Gross sections and electron microscopy showed that select tracts were hypomyelinated in adult PKU mouse forebrain but not hindbrain. The activity of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMGR), the rate controlling enzyme in the cholesterol biosynthetic pathway, was examined in isolated microsomes from forebrain, hindbrain, and liver to assess if perturbations in cholesterol biosynthesis were occurring. HMGR activity was normal in unaffected PKU hindbrain and was increased 2–4‐fold in PKU liver compared to control. HMGR activity in the forebrain, however, was decreased by 30%. Because normal numbers of MBP‐expressing glia (oligodendrocytes) were present, but the number of glia expressing HMGR was reduced by 40% in the hypomyelinated tracts, the decreased HMGR activity seemed to result from a down‐regulation of HMGR expression in affected oligodendrocytes. Exposure of an oligodendrocyte‐like glioma cell line to physiologically relevant elevated levels of Phe resulted in a 30% decrease in cholesterol synthesis, a 28% decrease in microsomal HMGR activity, and a 28% decrease in HMGR protein levels. Measurement of HMGR activity after addition of exogenous Phe to control brain microsomes revealed that Phe is a noncompetitive inhibitor of HMGR; physiologically relevant elevated levels of exogenous Phe inhibited HMGR activity by 30%. Taken together, these data suggest that HMGR is moderately inhibited in the PKU mouse. Unlike other cell types in the body, a subset of oligodendrocytes in the forebrain seems to be unable to overcome this inhibition. We speculate that this may be the cause of the observed pathology in PKU brain. J. Neurosci. Res. 61:549–563, 2000. © 2000 Wiley‐Liss, Inc.

Neuropathology of a 4‐month‐old infant born to a woman with phenylketonuria

“…26,27 Selected tracts were hypomyelinated in the forebrain, but not the hindbrain. 28 Moreover, elevated levels of phenylalanine inhibited cholesterol synthesis. 28 Hyperphenylalaninemia in neonatal rats also resulted in significantly reduced brain weight and whole brain levels of myelin lipids and proteins during the period of intensive myelinogenesis.…”

“…28 Moreover, elevated levels of phenylalanine inhibited cholesterol synthesis. 28 Hyperphenylalaninemia in neonatal rats also resulted in significantly reduced brain weight and whole brain levels of myelin lipids and proteins during the period of intensive myelinogenesis. [29][30][31] Recovery of corpus callosum was extensive when phenylalanine levels returned to normal; however, there remained a deficit in the number of myelinated axons in the cortical gray matter.…”

Brain dysfunction in phenylketonuria: Is phenylalanine toxicity the only possible cause?

“…When brain cells in culture were exposed to high phenylalanine concentrations in the medium, net protein synthesis was decreased (Hughes and Johnson 1976). High phenylalanine concentrations were also found to decrease the activity of HMG-CoA reductase, resulting in impaired cholesterol synthesis (Shefer et al 2000). As protein and cholesterol are essential parts of myelin, this finding is in line with observations of hypomyelination and gliosis in brain cells of PAH enu2 and wild -type mice (Dyer et al 1996) and in brains of deceased PKU patients (Bauman and Kemper 1982).…”

Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations

“…In this scenario, Nagasaka and colleagues [72] demonstrated that phenylketonuric patients have altered serum lipoprotein levels, including lower levels of total cholesterol, highdensity lipoprotein (HDL), low-density lipoprotein (LDL), and apolipoprotein A-I/A-II and B. These low cholesterol levels may be explained by the impairment of cholesterol synthesis due to down-regulated expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR; EC # 1.1.1.34), the rate controlling enzyme in the cholesterogenesis, as observed in a knock out murine model of PKU [73]. Furthermore, it has been demonstrated that Phe, PPA and PAA inhibit in vitro the activities of mevalonate 5-pyrophosphate decarboxylase (EC # 4.1.1.33) and HMGR in chicken liver at concentrations similar to those found in PKU patients [74].…”