The Physiological and Pathological Biophysics of Phase Separation and Gelation of RNA Binding Proteins in Amyotrophic Lateral Sclerosis and Fronto-Temporal Lobar Degeneration

Brain Res. 2018 Aug 15;1693(Pt A):11-23. doi: 10.1016/j.brainres.2018.04.036. Epub 2018 Apr 30.

Abstract

Many RNA binding proteins, including FUS, contain moderately repetitive, low complexity, intrinsically disordered domains. These sequence motifs have recently been found to underpin reversible liquid: liquid phase separation and gelation of these proteins, permitting them to reversibly transition from a monodispersed state to liquid droplet- or hydrogel-like states. This function allows the proteins to serve as scaffolds for the formation of reversible membraneless intracellular organelles such as nucleoli, stress granules and neuronal transport granules. Using FUS as an example, this review examines the biophysics of this physiological process, and reports on how mutations and changes in post-translational state alter phase behaviour, and lead to neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

Keywords: Amyotrophic lateral sclerosis; Arginine methylation; Cation-pi interactions; Frontotemporal dementia; Phase separation; RNA binding proteins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Biophysics / methods
  • Cytoplasmic Granules / metabolism
  • DNA-Binding Proteins / metabolism
  • Frontotemporal Dementia / genetics
  • Frontotemporal Lobar Degeneration / genetics*
  • Frontotemporal Lobar Degeneration / physiopathology*
  • Humans
  • Mutation
  • Neurodegenerative Diseases / pathology
  • Protein Domains
  • Protein Processing, Post-Translational
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / metabolism
  • RNA-Binding Proteins / metabolism
  • Temporal Lobe / metabolism

Substances

  • DNA-Binding Proteins
  • RNA-Binding Protein FUS
  • RNA-Binding Proteins