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):1671-1688. doi: 10.1016/j.jmb.2019.01.028. Epub 2019 Feb 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / metabolism
  • Amyotrophic Lateral Sclerosis / metabolism
  • DNA-Binding Proteins / metabolism*
  • Frontotemporal Dementia / metabolism
  • Humans
  • Models, Molecular
  • Protein Aggregation, Pathological / metabolism*
  • Protein Binding
  • RNA / metabolism*

Substances

  • Amyloid
  • DNA-Binding Proteins
  • TDP-43 protein, human
  • RNA