Figure 10. .

GFAP aggregation caused by the R416W mutation induces sHSP association and the association of ubiquitin as early events in the etiology of Alexander disease. The presence of the R416W GFAP mutation decreases the solubility of the GFAP filaments, probably by altering the filament-filament interactions in a manner that encourages aggregation. This is accompanied by the sequestration of the sHSP protein chaperones—αB-crystallin and HSP27 (shaded circles)—and GFAP into aggregates. Both proteins also localize to Rosenthal fibers, which also contain ubiquitin (Ub). The filament aggregates undergo a maturing process, with the additional posttranslational modification of integral components, such as the phosphorylation⁶⁴ and ubiquitination⁸ of αB-crystallin to form the Rosenthal fibers. The model is not exclusive to R416W GFAP, since Rosenthal fibers are a characteristic diagnostic feature of Alexander disease.¹² Other GFAP mutations differ in the details of the mechanism by which they produce aberrant filament-filament interactions leading to the formation of stabilized aggregates, but, once formed, they then follow a common pathway to Rosenthal fiber formation. Increased GFAP filament stability and the specific association of sHSPs are predicted to be the earliest events in the development of Alexander disease.