RNA as a key factor in driving or preventing self-assembly of the TAR DNA-binding protein 43
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Elsa Zacco Ricardo Graña-Montes Stephen R Martin Natalia Sanchez de Groot Caterina Alfano Gian Gaetano Tartaglia Annalisa PastoreAbstract
Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are incurable motor neuron diseases associated with muscle weakness, paralysis and respiratory failure. Accumulation of TAR DNA-binding protein 43 (TDP-43) as toxic cytoplasmic inclusions is one of the hallmarks of these pathologies. TDP-43 is an RNA-binding protein responsible for regulating RNA transcription, splicing, transport and translation. Aggregated TDP-43 does not retain its physiological function. Here, we exploit the ability of TDP-43 to bind specific RNA sequences to validate our hypothesis that the native partners of a protein can be used to interfere with its ability to self-assemble into aggregates. We propose that binding of TDP-43 to specific RNA can compete with protein aggregation. This study provides a solid proof of concept to the hypothesis that natural interactions can be exploited to increase protein solubility and could be adopted as a more general rational therapeutic strategy.
Journal details
Journal Journal of Molecular Biology
Volume 431
Issue number 8
Pages 1671-1688
Publication date
Full text links
Publisher website (DOI) 10.1016/j.jmb.2019.01.028
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Europe PubMed Central 30742796
Pubmed 30742796
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