From scaffold to effector: reframing GFAP in neurodegeneration - PubMed
2 hours ago
- #Biomarkers
- #Neurodegeneration
- #GFAP
- GFAP has evolved from a passive astrocytic marker to an active effector in neurodegenerative pathology.
- GFAP proteoforms, generated by alternative splicing and PTMs, play a role in cytoskeletal remodeling, inflammatory responses, proteostasis stress, and mitochondrial dysfunction.
- GFAP dysfunction is context-specific: primary toxicity in Alexander disease (AxD), intersects with amyloidogenic machinery in Alzheimer's disease (AD), and reflects inflammatory-metabolic coupling in FTD, PD, and ALS.
- Ultrasensitive plasma assays detect GFAP elevation years to decades before symptom onset, aiding early diagnosis.
- Therapeutic strategies include ASO-based modulation, targeting STAT3/NF-κB pathways, and restoring proteostasis via chaperone/autophagy.
- Future research needs isoform-/PTM-specific probes, conformational sensors, and spatial proteomic atlases validated in longitudinal cohorts.