A study published in the Redox Biology journal by the group led by Dr. Dolores Pérez-Sala at the Margarita Salas Center for Biological Research (CSIC) has shown that a mutation of Glial Fibrillary Acidic Protein (GFAP), associated with Alexander's disease increases the susceptibility of the protein and the cells that express it, to oxidative damage. Moreover, this mutant causes mitochondrial dysfunction and oxidative stress in a cellular model of the disease. Therefore, the study suggests that the oxidative damage caused by this mutant protein could contribute to the alterations in astrocytes that are distinctive of this disease.
GFAP is an essential component of astrocytes’ cytoskeleton, which plays multiple functions in their internal structural organization and dynamics, including organelle position and function. Mutations in GFAP lead to the severe rare disease known as Alexander disease, which has no cure. GFAP mutations alter astrocytes’ functions compromising their role in brain homeostasis, which results in neurodegeneration. Nevertheless, the mechanism of these alterations is not well understood.
Viedma-Poyatos et al. have employed cellular models to explore the consequences of expressing GFAP mutants. The study demonstrates that expression of the Alexander disease mutant, GFAP R239C, alters the cellular redox status and mitochondrial function, potentiates the formation of intracellular protein aggregates, and increases the susceptibility of astrocytes to oxidative damage, thus suggesting a pathogenic role for oxidative stress.
Detailed knowledge of the mechanisms underlying Alexander’s disease will help in the design of therapeutic strategies for the treatment of this pathology.
Reference: Alexander disease GFAP R239C mutant shows increased susceptibility to lipoxidation and elicits mitochondrial dysfunction and oxidative stress. Álvaro Viedma-Poyatos, Patricia González-Jiménez, María A. Pajares, Dolores Pérez-Sala. Redox Biol. 55, 102415. https://doi.org/10.1016/j.redox.2022.102415