ArticleProceedings of the National Academy of Sciences of the United States of America2021
GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 52 citations in OpenAlex.
- Elucidation of key lactylation- and palmitoylation-related genes and their related mechanisms in the development of neuropathic pain.Medicine · 2026Article
- The Activation of ARF1 Is Dynamically Regulated by its Palmitoylation.Molecular & cellular proteomics : MCP · 2026Article
- Overlapping pathways of migraine and the endocannabinoid system: Potential therapeutic targets.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Review
- Region-resolved proteomic map of the human brain: functional interconnections and neurological implications.Signal transduction and targeted therapy · 2026Article
- Cell type-resolved proteomics reveals intra- and intercellular signaling in Alzheimer's disease.bioRxiv : the preprint server for biology · 2026Article
- Protein S-acylation: Pathological mechanisms and novel therapeutic targets for diabetic complications.Chinese herbal medicines · 2026Review
- Article
- Regulatory Landscapes of Protein Acylations in Neuroinflammation: From Molecular Mechanisms to Therapeutic Targets.Neurochemical research · 2025Review
- Protein palmitoylation in hepatic diseases: Functional insights and therapeutic strategies.Journal of advanced research · 2025Review
- Recent advances in S-palmitoylation and its emerging roles in human diseases.Journal of hematology & oncology · 2025Review
- Deciphering the Structural Biology of GFAP: Connotations of Its Potency in Presaging the Diagnosis for Traumatic Brain Injury and AD.Neurology international · 2025Review
- Targeting glial fibrillary acidic protein in glaucoma: a monoclonal antibody approach to modulate glial reactivity and neuroinflammation for neuroprotection.Journal of neuroinflammation · 2025Article
- Palmitoylation in cardiovascular diseases: Molecular mechanism and therapeutic potential.International journal of cardiology. Heart & vasculature · 2025Review
- Activation of D2-like dopamine receptors improves the neuronal network and cognitive function of PPT1KI mice.Acta pharmacologica Sinica · 2025Article
- Palmitoylation by ZDHHC4 inhibits TRPV1-mediated nociception.EMBO reports · 2025Article
- The GFAP proteoform puzzle: How to advance GFAP as a fluid biomarker in neurological diseases.Journal of neurochemistry · 2025Review
- GFAP palmitoylcation mediated by ZDHHC23 in spinal astrocytes contributes to the development of neuropathic pain.Regional anesthesia and pain medicine · 2024Article
- Enhancing Gpx1 palmitoylation to inhibit angiogenesis by targeting PPT1.Redox biology · 2024Article
- Palmitoylation regulates myelination by modulating the ZDHHC3-Cadm4 axis in the central nervous system.Signal transduction and targeted therapy · 2024Article
- Inhibiting S-palmitoylation arrests metastasis by relocating Rap2b from plasma membrane in colorectal cancer.Cell death & disease · 2024Article
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Authors and funding
20 authors at 5 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
The homeostasis of protein palmitoylation and depalmitoylation is essential for proper physiological functions in various tissues, in particular the central nervous system (CNS). The dysfunction of PPT1 (PPT1-KI, infantile neuronal ceroid lipofuscinosis [INCL] mouse model), which catalyze the depalmitoylation process, results in serious neurodegeneration accompanied by severe astrogliosis in the brain. Endeavoring to determine critical factors that might account for the pathogenesis in CNS by palm-proteomics, glial fibrillary acidic protein (GFAP) was spotted, indicating that GFAP is probably palmitoylated. Questions concerning if GFAP is indeed palmitoylated in vivo and how palmitoylation of GFAP might participate in neural pathology remain unexplored and are waiting to be investigated. Here we show that GFAP is readily palmitoylated in vitro and in vivo; specifically, cysteine-291 is the unique palmitoylated residue in GFAP. Interestingly, it was found that palmitoylated GFAP promotes astrocyte proliferation in vitro. Furthermore, we showed that PPT1 depalmitoylates GFAP, and the level of palmitoylated GFAP is overwhelmingly up-regulated in PPT1-knockin mice, which lead us to speculate that the elevated level of palmitoylated GFAP might accelerate astrocyte proliferation in vivo and ultimately led to astrogliosis in INCL. Indeed, blocking palmitoylation by mutating cysteine-291 into alanine in GFAP attenuate astrogliosis, and remarkably, the concurrent neurodegenerative pathology in PPT1-knockin mice. Together, these findings demonstrate that hyperpalmitoylated GFAP plays critical roles in regulating the pathogenesis of astrogliosis and neurodegeneration in the CNS, and most importantly, pinpointing that cysteine-291 in GFAP might be a valuable pharmaceutical target for treating INCL and other potential neurodegenerative diseases.
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