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 .

Diseases
Validation

Diseases presenting "leukodystrophy" symptom

achondroplasia

adrenomyeloneuropathy

alexander disease

cadasil

canavan disease

carcinoma of the gallbladder

classical phenylketonuria

coats disease

fabry disease

gm1 gangliosidosis

krabbe disease

neonatal adrenoleukodystrophy

phenylketonuria

pyruvate dehydrogenase deficiency

wiskott-aldrich syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

This symptom has already been validated