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J Mol Biol. 2019 Apr 5;431(8):1671-1688. doi: 10.1016/j.jmb.2019.01.028. Epub 2019 Feb 8.

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

Author information

1
UK Dementia Research Institute at King's College London, London, SE5 9RT, United Kingdom; The Wohl Institute at King's College London, London, SE5 9RT, United Kingdom.
2
Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain.
3
The Francis Crick Institute, London, NW1 1AT, United Kingdom.
4
Fondazione Ri.MED, Palermo, 90133, Italy.
5
Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain; Institutio Catalan de Recerca I Estudis Avancats (ICREA), 23 Passeig Lluıs Companys, 08010 Barcelona, Spain; Department of Biology 'Charles Darwin', Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
6
UK Dementia Research Institute at King's College London, London, SE5 9RT, United Kingdom; The Wohl Institute at King's College London, London, SE5 9RT, United Kingdom; Scuola Normale Superiore, Piazza dei Cavalieri, Pisa, 56126, Italy. Electronic address: annalisa.pastore@crick.ac.uk.

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.

KEYWORDS:

RNA binding; amyotrophic lateral sclerosis; frontotemporal dementia; neurodegeneration; protein aggregation

PMID:
30742796
DOI:
10.1016/j.jmb.2019.01.028
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