Alexander disease is a rare but often fatal disease of the central nervous system. Infantile, juvenile and adult forms have been described that present with different clinical signs, but are unified by the characteristic presence in astrocytes of Rosenthal fibers-protein aggregates that contain glial fibrillary acidic protein (GFAP) and small stress proteins. The chance discovery that miceexpressing a human GFAP transgene formed abundant Rosenthal fibers suggested that mutations in the GFAP gene are a cause of Alexander disease. Sequencing results from several laboratories have indeed now identified GFAP coding mutations in most cases of the disease, including both the infantile and juvenile forms. These mutations have been found in the 1A, 2A and 2B segments of the conserved central roddomain of GFAP, and also in the variable tail region. All changes detected are heterozygous missense mutations, and none has been found in any parent of a patient that has been tested. This indicates that most cases of Alexander disease arise through de novo, dominant, GFAP mutations. Many of these mutations are homologous to ones described in other intermediate filament diseases. These otherdiseases have been attributed to a dominant loss of function, as the intermediate filament network is usually disrupted and a similar phenotype is observed in mice in which the corresponding intermediate filament gene has been inactivated. However, astrocytes of Alexander disease patients have normal appearing intermediate filaments, and GFAP null mice do not display the symptoms or pathology ofAlexander disease. Thus, Alexander disease likely results from a dominant gain of function. Drawing upon the homology of many of the Alexander disease mutations to those found in other intermediate filament diseases, it is suggested that the gain of function is due to a partial block of filament assembly that leads to accumulation of an intermediate that participates in toxic interactions.Mutations in the gene for the astrocyte specific intermediate filament, glial fibrillary acidic protein (GFAP), cause the rare leukodystrophy Alexander disease (AxD). To study the pathology of this primary astrocyte defect, we have generated knock-in mice with missense mutations homologous to those found in humans. In this report, we show that mice with GFAP-R76H and -R236H mutations develop Rosenthalfibers, the hallmark protein aggregates observed in astrocytes in AxD, in the hippocampus, corpus callosum, olfactory bulbs, subpial, and periventricular regions. Astrocytes in these areas appear reactive and total GFAP expression is elevated. Although general white matter architecture and myelination appear normal, when crossed with an antioxidant response element reporter line, the mutant mice showa distinct pattern of reporter-gene induction that is especially prominent in the corpus callosum, and histochemical staining reveals accumulation of iron in the same region. The mutant mice have a normal lifespan and show no overt behavioral defects, but are more susceptible to kainate-induced seizures. Although these mice demonstrate increased GFAP expression by themselves, further elevation ofGFAP via crosses to GFAP transgenic animals leads to a shift in GFAP solubility, an increased stress response, and ultimately death. The mice do not display the full spectrum of pathology observed in human infantile AxD, but may more closely resemble the adult form of the disease. These studies provide formal proof linking GFAP mutations with Rosenthal fibers and oxidative stress, and correlategliosis and GFAP protein levels to the severity of the disease.
Here, we describe the early events in the disease pathogenesis of Alexander disease. This is a rare and usually fatal neurodegenerative disorder whose pathological hallmark is the abundance of protein aggregates in astrocytes. These aggregates, termed "Rosenthal fibers," contain the protein chaperones alpha B-crystallin and HSP27 as...
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