Alexander disease mutant glial fibrillary acidic protein compromises glutamate transport in astrocytes.

[alexander disease]

Alexander disease (AxD ) is a leukodystrophy caused by heterozygous mutations in the gene for glial fibrillary acidic protein , an intermediate filament protein expressed by astrocytes . The mutation causes prominent protein aggregates inside astrocytes ; there is also loss of myelin and oligodendrocytes and neuronal degeneration . We show that immunohistochemical staining for glutamate transporter 1 , the major brain glutamate transporter expressed primarily in astrocytes suggests decreased levels in the hippocampi of infantile AxD patients . A knock-in mouse model of AxD also shows significant reduction of glutamate transporter 1 in the hippocampus . To explore this phenomenon at the cellular level , wild-type and R 239 C mutant glial fibrillary acidic proteins (the most common mutation ) were overexpressed in astrocytes in culture . Western blotting and whole-cell patch clamp recordings demonstrated that the R 239 C astrocytes exhibited markedly reduced glutamate transporter 1 protein levels ; this resulted in attenuated or abolished glutamate-induced inward transporter current . Neurons cocultured with the R 239 C astrocytes exhibited increased death after glutamate challenge . These results indicate that aberrant astrocytes have decreased glutamate uptake , which may play an important role in the pathogenesis of neuronal and oligodendrocyte injury and death in AxD .