Mutations in the astrocyte-specific intermediate filament, glial fibrillary acidic protein (GFAP), lead to the rare and fatal disorder, Alexander disease (AxD). A prominent feature of the disease is aberrant accumulation of GFAP. It has been proposed that this accumulation occurs due to an increase in gene transcription coupled with impaired proteasomal degradation, yet this hypothesis remains untested. We therefore sought to directly investigate GFAP turnover in a mouse model of AxD that is heterozygous for a disease-causing point mutation (GfapR236H/+) (and thus expresses both wild-type and mutant protein). Stable isotope labeling by amino acids in cell culture (SILAC), using primary cortical astrocytes, indicated that the in vitro half-lives of total GFAP in astrocytes from wild-type and mutant mice were similar, at ~3-4 days. Surprisingly, results obtained with stable isotope labeling of mammals (SILAM) revealed that, in vivo, the half-life of GFAP in mutant mice (15.4 &+- 0.5 days) was much shorter than that in wild-type mice (27.5 &+- 1.6 days). These unexpected in vivo data are most consistent with a model in which synthesis and degradation are both increased. Our work reveals that an AxD-causing mutation alters GFAP turnover kinetics in vivo, and provides an essential foundation for future studies aimed at preventing or reducing the accumulation of GFAP. In particular, these data suggest that elimination of GFAP might be possible, and occur more quickly than previously surmised.
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