Elevated GFAP isoform expression promotes protein aggregation and compromises astrocyte function.

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Alexander disease (AxD) is a neurodegenerative disorder linked to mutations in the glial fibrillary acidic protein (GFAP) gene.
• GFAP aggregation and Rosenthal fiber accumulation characterize AxD, but the precise pathogenic mechanisms remain unclear.
• Previous research suggests increased GFAP levels are central to AxD, with intronic mutations altering GFAP splicing.

Purpose of the Study:

• To investigate the role of increased GFAP isoform expression in Alexander disease pathogenesis.
• To determine if specific GFAP isoforms contribute to protein aggregation, astrocyte dysfunction, and neurodegeneration.

Main Methods:

• Primary astrocyte cultures were established from transgenic mice overexpressing human GFAP.
• In vitro assembly studies were performed using different GFAP isoforms (GFAP-α, -δ, -κ, -λ).
• Lentiviral transduction was used to assess the impact of minor GFAP isoforms on filament stability and aggregate formation.

Main Results:

• Transgenic astrocytes showed disproportionate increases in GFAP-δ and GFAP-κ isoforms, which were also found in human AxD brains.
• Minor GFAP isoforms (GFAP-δ, -κ, -λ) were aggregation-prone and compromised in vitro filament assembly compared to GFAP-α.
• Expression of minor GFAP isoforms led to the formation of Rosenthal fiber-like aggregates, decreased filament solubility, and disrupted intermediate filament networks.

Conclusions:

• Elevated expression of specific GFAP isoforms contributes to GFAP aggregation and astrocyte dysfunction in Alexander disease.
• Impaired glutamate transport by affected astrocytes has toxic effects on neighboring neurons, suggesting a non-cell-autonomous neurodegenerative mechanism.
• Findings link GFAP isoform dysregulation to key pathological features of AxD, offering insights into disease mechanisms.