ArticleASN neuro2013
Caspase cleavage of GFAP produces an assembly-compromised proteolytic fragment that promotes filament aggregation.
Article in ASN neuro, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
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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
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 56 citations in OpenAlex.
- Pooled it
- GFAP degradation in TBI: linking novel modified products to astrocyte pathology and patient outcome.Acta neuropathologica communications · 2026Article
- The Role of Glial Fibrillary Acidic Protein in the Neuropathology of Alzheimer's Disease and Its Potential as a Blood Biomarker for Early Diagnosis and Progression.Molecular neurobiology · 2025Review
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
- Deciphering the Structural Biology of GFAP: Connotations of Its Potency in Presaging the Diagnosis for Traumatic Brain Injury and AD.Neurology international · 2025Review
- Autophagy Regulates Müller Glial Cell Inflammatory Activation.Investigative ophthalmology & visual science · 2025Article
- Genotype-Phenotype Association for 14Neurology. Genetics · 2025Article
- Deletions in Glial Fibrillary Acidic Protein Leading to Alterations in Intermediate Filament Assembly and Network Formation.International journal of molecular sciences · 2025Article
- Spinal cord injury induces transient activation of hepatic stellate cells in rat liver.Scientific reports · 2025Article
- Morphological Characteristics and Extracellular Matrix Abnormalities in Astrocytes Derived From iPSCs of Children With Alexander Disease.CNS neuroscience & therapeutics · 2025Article
- Identification of a novel caspase cleavage motif AEAD.Virologica Sinica · 2024Article
- Advances in development of biomarkers for brain damage and ischemia.Molecular biology reports · 2024Review
- GFAP as Astrocyte-Derived Extracellular Vesicle Cargo in Acute Ischemic Stroke Patients-A Pilot Study.International journal of molecular sciences · 2024Article
- Neurovascular injury associated non-apoptotic endothelial caspase-9 and astroglial caspase-9 mediate inflammation and contrast sensitivity decline.Cell death & disease · 2022Article
- Characterization of Calpain and Caspase-6-Generated Glial Fibrillary Acidic Protein Breakdown Products Following Traumatic Brain Injury and Astroglial Cell Injury.International journal of molecular sciences · 2022Article
- 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
- Generation and Release of Neurogranin, Vimentin, and MBP Proteolytic Peptides, Following Traumatic Brain Injury.Molecular neurobiology · 2022Article
- 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
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 3 countries.
Funding
Abstract
IF (intermediate filament) proteins can be cleaved by caspases to generate proapoptotic fragments as shown for desmin. These fragments can also cause filament aggregation. The hypothesis is that disease-causing mutations in IF proteins and their subsequent characteristic histopathological aggregates could involve caspases. GFAP (glial fibrillary acidic protein), a closely related IF protein expressed mainly in astrocytes, is also a putative caspase substrate. Mutations in GFAP cause AxD (Alexander disease). The overexpression of wild-type or mutant GFAP promotes cytoplasmic aggregate formation, with caspase activation and GFAP proteolysis. In this study, we report that GFAP is cleaved specifically by caspase 6 at VELD²²⁵ in its L12 linker domain in vitro. Caspase cleavage of GFAP at Asp²²⁵ produces two major cleavage products. While the C-GFAP (C-terminal GFAP) is unable to assemble into filaments, the N-GFAP (N-terminal GFAP) forms filamentous structures that are variable in width and prone to aggregation. The effect of N-GFAP is dominant, thus affecting normal filament assembly in a way that promotes filament aggregation. Transient transfection of N-GFAP into a human astrocytoma cell line induces the formation of cytoplasmic aggregates, which also disrupt the endogenous GFAP networks. In addition, we generated a neo-epitope antibody that recognizes caspase-cleaved but not the intact GFAP. Using this antibody, we demonstrate the presence of the caspase-generated GFAP fragment in transfected cells expressing a disease-causing mutant GFAP and in two mouse models of AxD. These findings suggest that caspase-mediated GFAP proteolysis may be a common event in the context of both the GFAP mutation and excess.
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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.