ArticleThe Journal of biological chemistry2010
Oligomers of mutant glial fibrillary acidic protein (GFAP) Inhibit the proteasome system in alexander disease astrocytes, and the small heat shock protein alphaB-crystallin reverses the inhibition.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it, 100 citations in OpenAlex.
- A systematic review and meta-analysis of GFAP gene variants in Alexander disease.Scientific reports · 2024Pooled it
- Progressive gait and motor deficits in a rat model of Alexander disease.Behavioural brain research · 2026Article
- Synergistic Effects of Glial Fibrillary Acidic Protein Mutation and Overexpression in the Pathogenesis of Alexander Disease.International journal of molecular sciences · 2026Article
- Alexander disease mutations differentially sensitize glial fibrillary acidic protein (GFAP) to posttranslational modifications and network disruption by oxidants.Redox biology · 2026Article
- Deletions in Glial Fibrillary Acidic Protein Leading to Alterations in Intermediate Filament Assembly and Network Formation.International journal of molecular sciences · 2025Article
- Comparisons of neurodegenerative disease biomarkers across different biological fluids from patients with Huntington's disease.Journal of neurology · 2025Article
- Autophagy in brain tumors: molecular mechanisms, challenges, and therapeutic opportunities.Journal of translational medicine · 2025Review
- Article
- Autophagy in alzheimer disease pathogenesis and its therapeutic values.Autophagy reports · 2025Review
- Alexander disease: the road ahead.Neural regeneration research · 2023Review
- Effects of Alexander disease-associated mutations on the assembly and organization of GFAP intermediate filaments.Molecular biology of the cell · 2022Article
- The neurovascular unit in leukodystrophies: towards solving the puzzle.Fluids and barriers of the CNS · 2022Review
- Alexander disease: models, mechanisms, and medicine.Current opinion in neurobiology · 2022Review
- Crystallin Alpha-B Overexpression as a Possible Marker of Reactive Astrogliosis in Human Cerebral Contusions.Frontiers in cellular neuroscience · 2022Article
- A report of two cases of bulbospinal form Alexander disease and preliminary exploration of the disease.Molecular medicine reports · 2021Article
- Pathology of the neurovascular unit in leukodystrophies.Acta neuropathologica communications · 2021Article
- From structural resilience to cell specification - Intermediate filaments as regulators of cell fate.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Review
- All in Your Mind? New-Onset Dysphagia in a Previously Healthy Adolescent Child.Journal of pediatric intensive care · 2020Article
- Astrocyte-Oligodendrocyte-Microglia Crosstalk in Astrocytopathies.Frontiers in cellular neuroscience · 2020Review
- Refining the concept of GFAP toxicity in Alexander disease.Journal of neurodevelopmental disorders · 2019Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
The accumulation of the intermediate filament protein, glial fibrillary acidic protein (GFAP), in astrocytes of Alexander disease (AxD) impairs proteasome function in astrocytes. We have explored the molecular mechanism that underlies the proteasome inhibition. We find that both assembled and unassembled wild type (wt) and R239C mutant GFAP protein interacts with the 20 S proteasome complex and that the R239C AxD mutation does not interfere with this interaction. However, the R239C GFAP accumulates to higher levels and forms more protein aggregates than wt protein. These aggregates bind components of the ubiquitin-proteasome system and, thus, may deplete the cytosolic stores of these proteins. We also find that the R239C GFAP has a greater inhibitory effect on proteasome system than wt GFAP. Using a ubiquitin-independent degradation assay in vitro, we observed that the proteasome cannot efficiently degrade unassembled R239C GFAP, and the interaction of R239C GFAP with proteasomes actually inhibits proteasomal protease activity. The small heat shock protein, alphaB-crystallin, which accumulates massively in AxD astrocytes, reverses the inhibitory effects of R239C GFAP on proteasome activity and promotes degradation of the mutant GFAP, apparently by shifting the size of the mutant protein from larger oligomers to smaller oligomers and monomers. These observations suggest that oligomeric forms of GFAP are particularly effective at inhibiting proteasome activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.