RNA as a key factor in driving or preventing self-assembly of the TAR DNA-binding protein 43

Zacco, Elsa; Graña-Montes, Ricardo; Martin, Stephen R.; Sanchez de Groot, Natalia; Alfano, Caterina; Tartaglia, Gian Gaetano; Pastore, Annalisa

doi:http://dx.doi.org/10.1016/j.jmb.2019.01.028

RNA as a key factor in driving or preventing self-assembly of the TAR DNA-binding protein 43

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Zacco E, Graña-Montes R, Martin SR, de Groot NS, Alfano C, Tartaglia GG et al. RNA as a key factor in driving or preventing self-assembly of the TAR DNA-binding protein 43. J Mol Biol. 2019 Apr 5;431(8):1671-88. DOI: 10.1016/j.jmb.2019.01.028

Abstract

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.