Integrative transcriptome-wide association analyses reveal PRKCG-linked GABAergic dysfunction in Fragile X-associated...

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder linked to FMR1 gene CGG repeat expansions.
• The exact molecular mechanisms causing neurodegeneration in FXTAS are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying FXTAS pathogenesis.
• To identify key genes and cell types involved in FXTAS.

Main Methods:

• A multi-omics strategy and transcriptome-wide association studies (TWAS) were employed.
• Conditional mouse models expressing expanded CGG repeats in GABAergic neurons were utilized.
• Functional screening in Drosophila was performed.

Main Results:

• Brain-region-specific molecular signatures and significant gene dysregulation in inhibitory neurons were identified.
• Selective expression of expanded CGG repeats in GABAergic neurons mimicked FXTAS pathology in mice.
• PRKCG was identified as a genetic modifier of FXTAS, with evidence linking its overexpression to disease onset.
• hnRNPA2/B1 was found to sequester CGG repeat RNA, affecting numerous dysregulated mRNAs in GABAergic neurons.

Conclusions:

• GABAergic neurons play a critical role in the pathogenesis of FXTAS.
• PRKCG is a significant modulator of CGG repeat-associated neurotoxicity and a potential therapeutic target for FXTAS.