S. Shefer et al., Is there a relationship between 3-hydroxy-3-methylglutaryl coenzyme a reductase activity and forebrain pathology in the PKU mouse?, J NEUROSC R, 61(5), 2000, pp. 549-563
Previous reports have suggested that elevated levels of phenylalanine inhib
it cholesterol synthesis. The goals of this study were to investigate if pe
rturbations in cholesterol synthesis exist in the PAH(enu2) genetic mouse m
odel 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 hyp
omyelinated in adult PKU mouse forebrain but not hindbrain. The activity of
3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), the rate controlli
ng 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 un
affected PKU hindbrain and was increased 2-4-fold in PKU liver compared to
control. HMGR activity in the forebrain, however, was decreased by 30%, Bec
ause normal numbers of MBP-expressing glia (oligodendrocytes) were present,
but the number of glia expressing HMGR was reduced by 40% in the hypomyeli
nated tracts, the decreased HMGR activity seemed to result from a down-regu
lation of HMGR expression in affected oligodendrocytes, Exposure of an olig
odendrocytelike glioma cell line to physiologically relevant elevated level
s of Phe resulted in a 30% decrease in cholesterol synthesis, a 28% decreas
e in microsomal HMGR activity, and a 28% decrease in HMGR protein levels. M
easurement of HMGR activity after addition of exogenous Phe to control brai
n microsomes revealed that Phe is a noncompetitive inhibitor of HMGR; physi
ologically relevant elevated levels of exogenous Phe inhibited HMGR activit
y by 30%, Taken together, these data suggest that HMGR is moderately inhibi
ted in the PKU mouse. Unlike other cell types in the body, a subset of olig
odendrocytes in the forebrain seems to be unable to overcome this inhibitio
n. We speculate that this may be the cause of the observed pathology in PKU
brain. (C) 2000 Wiley-Liss, Inc.