Induced expression of expanded CGG RNA causes mitochondrial dysfunction in vivo

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder linked to premutation FMR1 gene carriers.
• The disease pathogenesis involves RNA gain-of-function toxicity due to expanded CGG repeats in the FMR1 gene.

Purpose of the Study:

• To investigate the in vivo pathogenesis of FXTAS using novel inducible transgenic mouse models.
• To elucidate the molecular mechanisms of CGG repeat RNA toxicity and its impact on cellular functions.

Main Methods:

• Development of Tet-On inducible transgenic mouse models expressing 11CGG or 90CGG repeats at the RNA level.
• Induction of transgene expression using doxycycline (dox) in mice bred to an hnRNP-rtTA driver line.
• Assessment of physiological changes (weight loss, mortality) and tissue pathology (liver steatosis, apoptosis) via immunohistochemistry.

Main Results:

• Mice expressing 90CGG RNA exhibited rapid weight loss and mortality upon dox induction, unlike 11CGG controls.
• Immunohistochemistry revealed liver steatosis and apoptosis in 90CGG mice, with decreased GPX1 and increased cytochrome C expression.
• Findings indicate that expanded CGG repeat expression, not normal repeat overexpression, causes pathology and mitochondrial dysfunction.

Conclusions:

• Expanded CGG repeat RNA expression in vivo leads to FXTAS-related pathology and mitochondrial dysfunction.
• The developed dox-inducible mouse models provide valuable tools for studying FXTAS pathogenesis and testing therapeutic interventions.