Evidence for central nervous system glial cell plasticity in phenylketonuria

J Neuropathol Exp Neurol. 1996 Jul;55(7):795-814. doi: 10.1097/00005072-199607000-00005.


Phenylketonuria (PKU) is caused by mutation(s) in the phenylalanine hydroxylase (PAH) gene which lead to deficient PAH activity and an accumulation of phenylalanine in the blood. The primary pathologic finding is hypomyelination and gliosis of central nervous system white matter. Similar white matter pathology is observed in the Pahenu2 mouse, a genetic model for PKU. We studied this mouse to examine the basis for these neuropathologic changes in PKU and to determine if hypomyelination and gliosis occur independently or are interrelated. Although white matter tracts within PKU brains are hypomyelinated, immunostaining and Western blot analyses revealed that these tracts contain abundant amounts of myelin markers, i.e. myelin basic protein (MBP), 2',3'-cyclic nucleotide 3'phosphohydrolase, and myelin/oligodendrocyte-specific protein (MOSP). However, Western blot analyses also showed that MBP isoform expression was aberrant. Investigation of individual cells was performed by extraction of tissue sections with Triton X-100. Most of the MOSP was extracted, with the remaining MOSP clearly visible in dual labeled cells, i.e. MOSP was colocalized along glial fibrillary acidic protein (GFAP) filaments. Cells expressing both MBP and GFAP were also identified in optic tract. Double labeling with a riboprobe for MBP and antibodies specific for GFAP revealed that the majority of GFAP-positive cells expressed MBP mRNA. Our in vitro studies examined the response of cultured wild type oligodendrocytes to elevated phenylalanine for 4 weeks (wk). Under these conditions, about 50 these conditions, about 50% of the oligodendrocytes expressed GFAP filaments and failed to elaborate membrane sheets. Proliferation of astrocytes appears not to be the source of gliosis, since the nuclei of GFAP-positive cells in the PKU brains did not immunostain for proliferating cell nuclear antigen. Dual-labeled cells were detected in normal mouse brain sections; however, PKU mouse white matter tracts were found to contain about twice the number of dual-labeled cells compared to normal tissue. Taken together, these data suggest that both myelinating and nonmyelinating oligodendrocytes are present in the normal adult brain, and that in response to a toxic factor such as elevated phenylalanine, myelinating oligodendrocytes adopt a nonmyelinating phenotype that expresses GFAP. Since myelinating Schwann cells and GFAP-positive nonmyelinating Schwann cells are normally present in adult peripheral nerve, and the myelinating Schwann cells react to pathologic situations by switching to GFAP-positive nonmyelinating cells, it may be that oligodendrocytes and Schwann cells are more similar than previously thought.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Animals
  • Biomarkers
  • Brain / pathology
  • Brain / physiopathology*
  • Glial Fibrillary Acidic Protein / metabolism
  • Gliosis / pathology
  • Humans
  • Mice
  • Mice, Mutant Strains / genetics
  • Mutation
  • Myelin Basic Protein / genetics
  • Myelin Sheath / metabolism
  • Myelin Sheath / ultrastructure
  • Neuroglia / physiology*
  • Neuronal Plasticity*
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology
  • Phenylalanine / blood
  • Phenylalanine Hydroxylase / genetics
  • Phenylketonurias / pathology
  • Phenylketonurias / physiopathology*
  • RNA, Messenger / metabolism


  • Biomarkers
  • Glial Fibrillary Acidic Protein
  • Myelin Basic Protein
  • RNA, Messenger
  • Phenylalanine
  • Phenylalanine Hydroxylase