Thus, our study suggested that mitochondria dynamically transferred between neural cells and revealed that AxD-associated mutations in GFAP gene disrupted the astrocytic transfer, providing a potential pathogenic mechanism in AxD.
This finding suggests that AxD onset is due to an intrinsic toxicity of the mutant GFAPinstead of it acting indirectly by being more stable than WT GFAP and thereby increasing the total GFAP level.
Alexander disease (AxD) is a leukodystrophy, described in infantile, juvenile and adult onset forms, due to mutations in the glial fibrillary acid protein (GFAP) gene.
Infantile Alexander disease is a rare progressive leukodystrophy caused by autosomal dominant mutations in the (GFAP) gene typically presenting with psychomotor retardation, progressive macrocephaly and refractory epilepsy.
Transcriptome analysis of astrocytes from a model of AxD showed age-dependent upregulation of GFAP, several markers for neurotoxic reactive astrocytes, and downregulation of Ca<sup>2+</sup> homeostasis molecules.
Furthermore, mapping of the GFAP mutations associated with Alexander disease reveals that most involve residues buried in the core of the interface, and are likely to disrupt the intermolecular interactions and/or introduce steric clashes, thereby decreasing GFAP solubility and promoting aggregation.
In this study, we use GFAP mutant mouse models of Alexander disease to test the efficacy of antisense suppression and evaluate the effects on molecular and cellular phenotypes and non-cell-autonomous toxicity.
These results reveal that AxD-causing mutations in GFAP disrupt intracellular vesicle regulation and impair astrocyte secretion, resulting in astrocyte dysfunction and AxD pathogenesis.
Our findings seem to suggest that the mechanism of development of AxD may not be due to a function gain due to increase of GFAP, but to failure in the differentiation process may occur at the stage in which precursor cells transform into oligodendrocytes, and that possibility may provide the best explanation for the clinical and radiological images described in AxD.
We have been studying the astrocytes of Alexander disease (AxD), which is caused by heterozygous mutations in the GFAP gene, which is the gene that encodes the major astrocyte intermediate filament protein.
Nineteen AxD patients with GFAP mutation were compared with 14 patients negative forGFAP mutation in whom AxD was suspected due to "atrophy of the medulla oblongata."
Our work reveals that an AxD-causing mutation alters GFAP turnover kinetics <i>in vivo</i> and provides an essential foundation for future studies aimed at preventing or reducing the accumulation of GFAP.