An integrative study on ribonucleoprotein condensates identifies scaffolding RNAs and reveals a new player in Fragile X-associated Tremor/Ataxia Syndrome

Recent evidence indicates that specific RNAs promote formation of ribonucleoprotein condensates by acting as scaffolds for RNA-binding proteins (RBPs). We systematically investigated RNA-RBP interaction networks to understand ribonucleoprotein assembly. We found that highly-contacted RNAs are highly...

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Published inbioRxiv
Main Authors Cid-Samper, Fernando, Gelabert-Baldrich, Iona, Lang, Benjamin, Lorenzo-Gotor, Nieves, Riccardo Delli Ponti, Lies-Anne Wfm Severijnen, Bolognesi, Benedetta, Gelpi, Ellen, Hukema-Felten, Renate K, Botta-Orfila, Teresa, Tartaglia, Gian Gaetano
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 12.11.2018
Subjects
3' Untranslated regions
Ataxia
Condensates
FMR1 protein
Fragile X syndrome
Intellectual disabilities
Neurodegenerative diseases
Proteins
Ribonucleic acid
RNA
RNA-binding protein
Splicing
Therapeutic applications
Tremor
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Summary:Recent evidence indicates that specific RNAs promote formation of ribonucleoprotein condensates by acting as scaffolds for RNA-binding proteins (RBPs). We systematically investigated RNA-RBP interaction networks to understand ribonucleoprotein assembly. We found that highly-contacted RNAs are highly structured, have long untranslated regions (UTRs) and contain nucleotide repeat expansions. Among the RNAs with such properties, we identified the FMR1 3' UTR that harbors CGG expansions implicated in Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). We studied FMR1 binding partners in silico and in vitro and prioritized the splicing regulator TRA2A for further characterization. In a FXTAS cellular model we validated TRA2A-FRM1 interaction and investigated implications of its sequestration at both transcriptomic and post-transcriptomic levels. We found that TRA2A co-aggregates with FMR1 in a FXTAS mouse model and in post mortem human samples. Our integrative study identifies key components of ribonucleoprotein aggregates, providing links to neurodegenerative disease and allowing the discovery of new therapeutic targets. Footnotes * Several parts of the main text and supplementary have been rewritten
DOI:10.1101/298943