From scaffold to effector: reframing GFAP in neurodegeneration.

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Neurodegenerative disorders present a significant global health challenge with limited disease-modifying treatments.
• Glial fibrillary acidic protein (GFAP) is increasingly recognized not just as a marker but as an active participant in neurodegenerative pathology.

Purpose of the Study:

• To review mechanistic and translational evidence establishing GFAP as a proteoform-governed hub.
• To highlight GFAP's potential for biomarker-guided precision interventions in neurodegenerative diseases.

Main Methods:

• Comprehensive literature search of mechanistic, pathological, and clinical studies using predefined keywords and inclusion criteria.
• Synthesis of evidence on GFAP proteoforms, including alternative splicing and post-translational modifications (PTMs).
• Analysis of GFAP's role in integrating cytoskeletal dynamics, inflammation, proteostasis, and mitochondrial function.

Main Results:

• GFAP proteoforms dictate astrocyte state transitions, influencing neuronal vulnerability and synaptic function.
• GFAP dysfunction is implicated in Alexander disease (AxD), while specific isoforms interact with amyloid in Alzheimer's disease (AD).
• GFAP elevation in plasma, detected years before symptom onset, serves as an early biomarker, complementing NfL and AT(N) markers.

Conclusions:

• GFAP proteoforms are central to neurodegenerative processes, linking astrocyte biology to neuronal damage.
• Therapeutic strategies targeting GFAP, including ASO modulation and pathway-specific interventions, show promise for precision medicine.
• Further development of isoform- and PTM-specific tools is crucial for advancing GFAP-based diagnostics and therapeutics in neurodegeneration.