ArticleExperimental cell research2011
Alexander disease causing mutations in the C-terminal domain of GFAP are deleterious both to assembly and network formation with the potential to both activate caspase 3 and decrease cell viability.
Article in Experimental cell research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 41 citations in OpenAlex.
- Adult-Onset Alexander Disease Presenting as Atypical Parkinsonism and Autonomic Dysfunction: A Case Series.Journal of clinical medicine · 2026Article
- GFAP degradation in TBI: linking novel modified products to astrocyte pathology and patient outcome.Acta neuropathologica communications · 2026Article
- Deciphering the Structural Biology of GFAP: Connotations of Its Potency in Presaging the Diagnosis for Traumatic Brain Injury and AD.Neurology international · 2025Review
- Deletions in Glial Fibrillary Acidic Protein Leading to Alterations in Intermediate Filament Assembly and Network Formation.International journal of molecular sciences · 2025Article
- Effects of Alexander disease-associated mutations on the assembly and organization of GFAP intermediate filaments.Molecular biology of the cell · 2022Article
- Alexander disease: models, mechanisms, and medicine.Current opinion in neurobiology · 2022Review
- Single-synapse analyses of Alzheimer's disease implicate pathologic tau, DJ1, CD47, and ApoE.Science advances · 2021Article
- Antisense therapy in a rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment.Science translational medicine · 2021Article
- A report of two cases of bulbospinal form Alexander disease and preliminary exploration of the disease.Molecular medicine reports · 2021Article
- Relative stabilities of wild-type and mutant glial fibrillary acidic protein in patients with Alexander disease.The Journal of biological chemistry · 2019Article
- Towards genomic database of Alexander disease to identify variations modifying disease phenotype.Scientific reports · 2019Article
- Alexander disease: an astrocytopathy that produces a leukodystrophy.Brain pathology (Zurich, Switzerland) · 2018Review
- Aggregation-prone GFAP mutation in Alexander disease validated using a zebrafish model.BMC neurology · 2017Article
- Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms.Acta neuropathologica · 2017Review
- Glial fibrillary acidic protein exhibits altered turnover kinetics in a mouse model of Alexander disease.The Journal of biological chemistry · 2017Article
- Characterization of a panel of monoclonal antibodies recognizing specific epitopes on GFAP.PloS one · 2017Article
- The role of gigaxonin in the degradation of the glial-specific intermediate filament protein GFAP.Molecular biology of the cell · 2016Article
- GFAP isoforms control intermediate filament network dynamics, cell morphology, and focal adhesions.Cellular and molecular life sciences : CMLS · 2016Article
- Functional characterization of a GFAP variant of uncertain significance in an Alexander disease case within the setting of an individualized medicine clinic.Clinical case reports · 2016Article
- Identification of a novel nonsense mutation in the rod domain of GFAP that is associated with Alexander disease.European journal of human genetics : EJHG · 2015Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
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Abstract
Alexander disease is a primary genetic disorder of astrocyte caused by dominant mutations in the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP). While most of the disease-causing mutations described to date have been found in the conserved α-helical rod domain, some mutations are found in the C-terminal non-α-helical tail domain. Here, we compare five different mutations (N386I, S393I, S398F, S398Y and D417M14X) located in the C-terminal domain of GFAP on filament assembly properties in vitro and in transiently transfected cultured cells. All the mutations disrupted in vitro filament assembly. The mutations also affected the solubility and promoted filament aggregation of GFAP in transiently transfected MCF7, SW13 and U343MG cells. This correlated with the activation of the p38 stress-activated protein kinase and an increased association with the small heat shock protein (sHSP) chaperone, αB-crystallin. Of the mutants studied, D417M14X GFAP caused the most significant effects both upon filament assembly in vitro and in transiently transfected cells. This mutant also caused extensive filament aggregation coinciding with the sequestration of αB-crystallin and HSP27 as well as inhibition of the proteosome and activation of p38 kinase. Associated with these changes were an activation of caspase 3 and a significant decrease in astrocyte viability. We conclude that some mutations in the C-terminus of GFAP correlate with caspase 3 cleavage and the loss of cell viability, suggesting that these could be contributory factors in the development of Alexander disease.
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