Review ArticleGFAP and its role in Alexander disease
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.
References (82)
- et al.
Infantile Alexander disease: spectrum of GFAP mutations and genotype–phenotype correlation
Am. J. Hum. Genet.
(2001) - et al.
Intermediate filament protein partnership in astrocytes
J. Biol. Chem.
(1999) - et al.
Characterization of human cDNA and genomic clones for glial fibrillary acidic protein
Brain Res. Mol. Brain Res.
(1990) - et al.
Early mitochondrial dysfunction in an infant with Alexander disease
Pediatr. Neurol.
(2006) - et al.
TRH therapy in a patient with juvenile Alexander disease
Brain Dev.
(2006) - et al.
Novel mutation of gene coding for glial fibrillary acidic protein in a Japanese patient with Alexander disease
Brain Dev.
(2006) - et al.
Plectin regulates the organization of glial fibrillary acidic protein in Alexander disease
Am. J. Pathol.
(2006) - et al.
Synergistic effects of the SAPK/JNK and the proteasome pathway on glial fibrillary acidic protein (GFAP) accumulation in Alexander disease
J. Biol. Chem.
(2006) - et al.
An autocrine/paracrine loop linking keratin 14 aggregates to tumor necrosis factor alpha-mediated cytotoxicity in a keratinocyte model of epidermolysis bullosa simplex
J. Biol. Chem.
(2004) - et al.
αB-crystallin is expressed in non-lenticular tissues and accumulates in Alexander's disease brain
Cell
(1989)
Translocation and induction of alpha B crystallin by heat shock in rat glioma (GA-1) cells
Biochem. Biophys. Res. Commun.
Formation of GFAP cytoplasmic inclusions in astrocytes and their disaggregation by alphaB-crystallin [in process citation]
Am. J. Pathol.
Identification and cloning of an mRNA coding for a germ cell-specific A-type lamin in mice
Exp. Cell Res.
An alternative splicing product of the lamin A/C gene lacks exon
J. Biol. Chem.
Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C
J. Biol. Chem.
Mouse peripherin isoforms
Biol. Cell
The mouse synemin gene encodes three intermediate filament proteins generated by alternative exon usage and different open reading frames
Exp. Cell Res.
A new splice variant of glial fibrillary acidic protein, GFAP epsilon, interacts with the presenilin proteins
J. Biol. Chem.
A novel glial fibrillary acidic protein messenger-rna lacking exon-1
Mol. Brain Res.
Autosomal dominant palatal myoclonus and spinal cord atrophy
J. Neurol. Sci.
A case of adult-onset Alexander disease with Arg416Trp human glial fibrillary acidic protein gene mutation
Neurosci. Lett.
Progressive skeletal myopathy, a phenotypic variant of desmin myopathy associated with desmin mutations
Neuromuscul. Disord.
A juvenile-onset, progressive cataract locus on chromosome 3q21–q22 is associated with a missense mutation in the beaded filament structural protein-2
Am. J. Hum. Genet.
Aspirin-induced blockade of NF-kappaB activity restrains up-regulation of glial fibrillary acidic protein in human astroglial cells
Biochim. Biophys. Acta
Alexander disease: GFAP mutations unify young and old
Lancet Neurol.
Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant
Brain
Alexander's disease: a report and reappraisal
Neurology
Alexander's disease in infancy and childhood: a report of two cases
Acta Neuropathol. (Berl.)
Infantile and juvenile presentations of Alexander's disease: a report of two cases
Acta Neurol. Scand.
Rosenthal fibers share epitopes with alpha B-crystallin, glial fibrillary acidic protein, and ubiquitin, but not with vimentin. Immunoelectron microscopy with colloidal gold
Am. J. Pathol.
On-grid immunogold labeling of glial intermediate filaments in epoxy-embedded tissue
Am. J. Anat.
Molecular interactions in intermediate-sized filaments revealed by chemical cross-linking. Heteropolymers of vimentin and glial filament protein in cultured human glioma cells
Eur. J. Biochem.
Molecular cloning and primary structure of human glial fibrillary acidic protein
Proc. Natl. Acad. Sci. U. S. A.
Structure of the mouse glial fibrillary acidic protein gene: Implications for the evolution of the intermediate filament multigene family
Nucleic Acids Res.
Expression specificity of GFAP transgenes
Neurochem. Res.
Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease
Nat. Genet.
Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice
Am. J. Pathol.
Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease
Ann. Neurol.
Alexander Disease
Alexander disease: not just a leukodystrophy anymore
Neurology
Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord
Neurology
Cited by (169)
Practical Genetics for the Neuroradiologist: Adding Value in Neurogenetic Disease
2022, Academic RadiologyAstrocyte-immune cell interactions in physiology and pathology
2021, ImmunityCitation Excerpt :A unifying feature of these three classes is that reactive astrocytes emerge in response to external stimuli. In contrast to this are “disease” astrocytes that could have altered transcriptomic, proteomic, and functional features due to an inherent disease-causing mutation (e.g., glial fibrillary acidic protein [GFAP] mutations in Alexander’s disease; Alexander, 1949; Quinlan et al., 2007). Although it is true that disease astrocytes could also react to pathological stimuli and become reactive, disease astrocytes themselves are not necessarily reactive at baseline.
Traumatic brain injury: Glial fibrillary acidic protein posttranslational modification
2020, Biomarkers for Traumatic Brain Injury