Elsevier

Experimental Cell Research

Volume 313, Issue 10, 10 June 2007, Pages 2077-2087
Experimental Cell Research

Review Article
GFAP and its role in Alexander disease

https://doi.org/10.1016/j.yexcr.2007.04.004Get rights and content

Abstract

Here we review how GFAP mutations cause Alexander disease. The current data suggest that a combination of events cause the disease. These include: (i) the accumulation of GFAP and the formation of characteristic aggregates, called Rosenthal fibers, (ii) the sequestration of the protein chaperones αB-crystallin and HSP27 into Rosenthal fibers, and (iii) the activation of both Jnk and the stress response. These then set in motion events that lead to Alexander disease. We discuss parallels with other intermediate filament diseases and assess potential therapies as part of this review as well as emerging trends in disease diagnosis and other aspects concerning GFAP.

Section snippets

Alexander disease—a brief overview

Alexander disease (OMIM #203450) was first described by W. S. Alexander [1]. It is a rare, but often fatal neurological disorder that has been divided into three subtypes based on the age of onset (Table 1): the infantile, juvenile and adult forms [2]. The infantile form, with onset between birth and about 2 years of age, is currently the most common form of the disease [3], [4], [5]. The characteristic neuropathological feature of all forms of Alexander's disease is the presence of Rosenthal

Update on GFAP mutations and their origins

A recent study [16] significantly expanded the number of Alexander disease mutations that have been published for GFAP, and other isolated case reports or small groups of patients continue to appear in the literature. The current status of GFAP mutations is shown in Fig. 1. The mutation hot spots in GFAP contain CpG dinucleotides which are substrates for methylation-induced deamination [21] and include the R79 position, which is the same arginine in the LNDR-motif that is frequently mutated in

Model systems

The discovery of the GFAP mutations paved the way to develop model systems in tissue culture cells and transgenic mice to study Alexander disease. Previous observations about the disease, such as the accumulation of GFAP in Rosenthal fibers along with several stress proteins, including αB-crystallin and HSP27, and the phosphorylation and ubiquitination of the Rosenthal fiber components, are all clues about the disease mechanism. Several appealing hypotheses have been suggested concerning the

GFAP mutants alter filament properties

When R239C GFAP was expressed into SW13Vim cells, the protein tended not to form filaments, but instead gave diffuse staining patterns comprising many distinct, variable foci [35]. This GFAP material was more resistant to extraction with Triton containing buffers. The results of the in vitro assembly revealed that while the GFAP still retained the ability to assemble, the filaments appeared less uniform and also had the tendency to pellet more efficiently in sedimentation assays. When

GFAP mutants trigger the stress response

One of the downstream consequences of the expression of R239C GFAP is the activation of the stress kinases Jnk and the upstream mixed lineage kinases (MLK) MLK2 and 3 and ASK1 [36]. The coexpression of a dominant negative Jnk along with both wild type and R239 GFAP tagged constructs restored the extraction of GFAP into low ionic strength, Triton-containing buffers. Some of the downstream consequences of GFAP overexpression included a compromised ubiquitin–proteosome system and the accumulation

Chaperone sequestration—a feature of Rosenthal fibers and a factor in disease progression

One of the consistent features of the disease is the overexpression of αB-crystallin [15], [43], [44]. This is also a consistent feature of recent animal [31] and cell models [36], [37] that suggests another facet to Alexander disease development. The sequestration of both HSP27 and αB-crystallin into the aggregates of GFAP will likely attenuate the ability of the astrocytes to resist stress [45], [46], [47] and prevent apoptosis [48]. In a recent cell model that investigated the consequences

Alternative spliced forms of GFAP and their function

Most intermediate filament genes are not alternatively spliced, but there are notable exceptions and these include LAMA [51], [52], [53], [54], peripherin [55], [56] and DNM (synemin; [57]). GFAP is also alternatively spliced ([58], [59], [60], [61], [62], [63]; Table 2), involving the 5′ UTR (β-GFAP), exon 6 (Δ6, Δ135, Δ164; [62]) and exon 7 (δ-/ε-GFAP [59], [60] and κ-GFAP [61]). The relative abundance of these GFAP transcripts is often low [61] and can be dependent upon astrocyte location

Acknowledgment

The financial support of the National Institutes of Health (NS42803) is gratefully acknowledged.

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