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Detection of Alternative Splicing During Epithelial-Mesenchymal Transition
Published on: October 9, 2014
Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients
Chantal Sellier1, Frédérique Rau, Yilei Liu
1Department of Neurobiology and Genetics, IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, Illkirch, France.
Abstract:
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder caused by expansion of 55-200 CGG repeats in the 5'-UTR of the FMR1 gene. FXTAS is characterized by action tremor, gait ataxia and impaired executive cognitive functioning. It has been proposed that FXTAS is caused by titration of RNA-binding proteins by the expanded CGG repeats. Sam68 is an RNA-binding protein involved in alternative splicing regulation and its ablation in mouse leads to motor coordination defects. Here, we report that mRNAs containing expanded CGG repeats form large and dynamic intranuclear RNA aggregates that recruit several RNA-binding proteins sequentially, first Sam68, then hnRNP-G and MBNL1. Importantly, Sam68 is sequestered by expanded CGG repeats and thereby loses its splicing-regulatory function. Consequently, Sam68-responsive splicing is altered in FXTAS patients. Finally, we found that regulation of Sam68 tyrosine phosphorylation modulates its localization within CGG aggregates and that tautomycin prevents both Sam68 and CGG RNA aggregate formation. Overall, these data support an RNA gain-of-function mechanism for FXTAS neuropathology, and suggest possible target routes for treatment options.
Insights
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) involves CGG repeat expansion in the FMR1 gene. Expanded repeats sequester RNA-binding proteins like Sam68, disrupting splicing and causing neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder linked to expanded CGG repeats in the FMR1 gene.
- FXTAS symptoms include tremor, gait ataxia, and cognitive deficits, potentially caused by RNA-binding protein titration.
- Sam68, an RNA-binding protein crucial for splicing, is implicated due to its role in motor coordination.
Purpose of the Study:
- To investigate the mechanism of FXTAS neuropathology.
- To determine the role of RNA-binding proteins, specifically Sam68, in CGG repeat-induced cellular dysfunction.
- To explore potential therapeutic targets for FXTAS.
Main Methods:
- Analysis of intranuclear RNA aggregates formed by expanded CGG repeats.
- Investigation of RNA-binding protein recruitment to these aggregates, focusing on Sam68, hnRNP-G, and MBNL1.
- Assessment of Sam68's splicing regulatory function and its alteration in FXTAS patients.
- Examination of Sam68 tyrosine phosphorylation and its effect on aggregate localization.
- Testing the effect of tautomycin on aggregate formation.
Main Results:
- Expanded CGG repeat mRNAs form dynamic intranuclear aggregates that sequentially recruit Sam68, hnRNP-G, and MBNL1.
- Sam68 is sequestered within these aggregates, leading to loss of its splicing regulatory function.
- Sam68-responsive splicing patterns are altered in FXTAS patients.
- Sam68 tyrosine phosphorylation influences its localization within CGG aggregates.
- Tautomycin treatment inhibits both Sam68 and CGG RNA aggregate formation.
Conclusions:
- The findings support an RNA gain-of-function mechanism in FXTAS neuropathology.
- Sam68 sequestration and subsequent disruption of splicing are key events in FXTAS.
- Modulating Sam68 localization and preventing aggregate formation represent potential therapeutic strategies for FXTAS.
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