Association of JC virus large T antigen with myelin basic protein transcription factor (MEF-1/Pur alpha) in hypomyelinated brains of mice transgenically expressing T antigen

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating d isease caused by cytolytic destruction of oligodendrocytes, the myelin-prod ucing cells of the central nervous system, by the human neurotropic JC viru s (JCV). The early protein of JCV, T antigen, which is produced at the earl y stage of infection, is important for orchestrating the events leading to viral lytic infection and cytolytic destruction of oligodendrocytes. Result s from transgenic mouse studies, however, have revealed that, in the absenc e of lytic infection, this protein can induce brain hypomyelination and sup pression of myelin gene expression. Since expression of the gene encoding m yelin basic protein, the major component of myelin, can be regulated by a D NA-binding transcription factor, MEF-1/Pur alpha, (Pur alpha), we have exam ined the level of this protein in transgenic mouse brains. Results from imm unoprecipitation and Western blots showed that while there was no drastic d ecrease in the level of MEF-1/Pur alpha in transgenic mouse brains, JCV T a ntigen was found in a complex with MEF-1/Pur alpha. Immunohistological stud ies revealed abnormal oligodendrocytes in white matter, where MEF-1/Pur alp ha and T antigen were detected. Furthermore, immunogold electron microscopi c studies revealed that Furor and T antigen are colocalized in the nucleus of the oligodendrocytes and in hippocampal neurons. Interestingly, results from cell culture studies revealed that incubation of oligodendrocytes with JCV led to a drastic decrease in the level of MEF-1/Pur alpha protein. The se observations provide insight into the molecular pathogenesis of PML and support a model for a dual effect of JCV on inducing hypomyelination by (i) affecting myelin gene expression via interaction of JCV T antigen and the myelin gene transcription factor, MEF-1/Pur alpha, and (ii) causing a decli ne in the level of the host regulatory proteins, including MEF-1/Pur alpha, which are involved in myelin gene expression.