Glial fibrillary acidic protein (GFAP) has evolved from a structural astrocytic marker into an active driver and translational biomarker in neurodegeneration. Alternative splicing and posttranslational modifications (PTMs) generate diverse GFAP isoforms/proteoforms (e.g., GFAPα/δ/λ), forming a “proteoform code” that shapes filament organization and astrocyte reactivity ( molecular diversity ). Pathological GFAP remodeling (including Rosenthal fibers) links astrocytic cytoskeletal stress to mitochondrial dysfunction and neuroinflammation, exemplified by the GFAP-Drp1 axis, JAK2/STAT3 signaling, and complement-associated synaptic injury ( pathogenic cascade ). ultrasensitive assays enable plasma GFAP quantification years before symptom onset, supporting an expanded A/T/N/G framework and biomarker-guided stratification of AD versus non-AD dementias ( clinical translation ). Collectively, the figure highlights GFAP as a proteoform-defined hub connecting mechanistic pathology to early diagnosis and precision therapeutic opportunities. • This review reframes glial fibrillary acidic protein (GFAP) from a passive astrocyte marker to a multifaceted, active effector in neurodegeneration • A complex “proteoform code,” comprising multiple GFAP isoforms and post-translational modifications, dictates its pathogenic functions. • GFAP mutations are causal in disease, directly driving mitochondrial fragmentation and bioenergetic failure in astrocytes. • This new understanding solidifies GFAP’s role as a key biomarker and establishes it as a promising therapeutic target for neurodegenerative diseases. Neurodegenerative disorders impose a growing global burden, yet disease-modifying therapies remain limited. Glial fibrillary acidic protein (GFAP) has shifted from a passive astrocytic marker to an active effector shaping neurodegenerative pathology. of Review: This review synthesizes mechanistic and translational evidence that defines GFAP as a proteoform-governed hub and highlights its value for biomarker-guided precision intervention. Key Scientific Concepts of Review: An extensive literature search across major databases was conducted using predefined keywords and strict inclusion criteria, covering mechanistic, pathological, and clinical studies. Evidence supports a GFAP proteoform code in which alternative splicing generates functionally distinct isoforms and PTMs encode context-dependent assembly dynamics and signaling outputs. We summarize how GFAP proteoforms integrate cytoskeletal remodeling with inflammatory transcriptional programs (notably STAT3 and NF-κB), proteostasis stress, and mitochondrial dysfunction, thereby coupling astrocyte state transitions to neuronal vulnerability and synaptic impairment. Disease trajectories are context specific: GFAP dysfunction drives primary toxicity in Alexander disease (AxD); in Alzheimer’s disease (AD), isoform-specific mechanisms intersect with amyloidogenic machinery and track early preclinical astrocyte activation; and in frontotemporal dementia (FTD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), GFAP reflects inflammatory–metabolic coupling during progression. Translationally, ultrasensitive plasma assays reveal GFAP elevation years to decades before symptom onset, complementing NfL and amyloid/tau within AT(N)-oriented diagnostic frameworks. Therapeutically, we evaluate precision strategies beyond global suppression, including ASO-based modulation, targeting STAT3/NF-κB-driven reactive programs, and restoring proteostasis via chaperone/autophagy pathways. Future progress hinges on isoform-/PTM-specific probes, conformational sensors, and spatial proteomic atlases validated in prospective longitudinal cohorts. In conclusion, GFAP represents both a mechanistic driver and a scalable biomarker, offering a translationally actionable axis to advance precision medicine in neurodegeneration.
Lu et al. (Sun,) studied this question.