GFAP and its role in Alexander disease

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 alpha B-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.

Figure 1

Features of Alexander disease. A. MR image of a 10-year-old boy with Alexander disease, showing extensive abnormalities (*) of the cerebral white matter with frontal predominance. (generously provided by Dr. Marjo van der Knaap [17]). Reprinted with permission from Elsevier. B. Rosenthal fibres (arrows) concentrated in the astrocytic endfeet surrounding a blood vessel (V) in the brain stem of a 1-year-old child with Alexander disease. Hematoxylin & eosin stain, paraffin section. Reprinted with permission from Elsevier [81]. C. Rosenthal fibres (arrows) surrounded by intermediate filaments (arrowheads) in an astrocyte cell body from a 17-month old child with Alexander disease, viewed by transmission electron microscopy (reprinted from [82], with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.).

Figure 2

Location of Alexander disease-associated mutations in GFAP in relation to protein domain structure of intermediate filaments. The red boxes indicate the four α-helical sub-domains within the central rod domain, separated by non-helical linkers. The grey boxes at the ends of helix 1A and 2B reflect the location of the highly conserved LNDR- and TYRKLLEGE-motifs and correspond to residues L76-R79 and T365-E373 respectively in GFAP. Each letter (on the right) represents an individual patient, using the single letter code for the mutated amino acid. Multiple letters adjacent to numbered residues indicate the number of independent mutations linked to that residue. Only one letter is shown for familial patients or identical twins. Symbols are color coded for clinical category based on age of onset (infantile, juvenile, or adult). A boxed letter indicates that this mutation was inherited and found in multiple family members. If a particular family with an inherited mutation contained affected individuals with variable phenotypes (for instance, some juvenile, and some adult), the classification for the proband only is shown. A circle around a mutation indicates that the patient was asymptomatic at the time of diagnosis. Mutations or polymorphisms shown on the left are presently considered innocuous and not responsible for disease (although there is one report of putative Alexander disease in a patient with E223Q). The diagram includes all patients published as of 1/07, as well as some unpublished patients. A continually updated list of mutations, along with links to the relevant publications, is available at the Alexander disease web site maintained at the University of Wisconsin-Madison (www.waisman.wisc.edu/alexander).