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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1671-1688
Number of pages18
JournalJournal of Molecular Biology
Volume431
Issue number8
DOIs
Publication statusPublished - 5 Apr 2019

Keywords

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

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