TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics

Neuron. 2017 Aug 16;95(4):808-816.e9. doi: 10.1016/j.neuron.2017.07.025.

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10-6). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions. TIA1 mutations significantly increased the propensity of TIA1 protein to undergo phase transition. In live cells, TIA1 mutations delayed stress granule (SG) disassembly and promoted the accumulation of non-dynamic SGs that harbored TDP-43. Moreover, TDP-43 in SGs became less mobile and insoluble. The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS/FTD pathogenesis.

Keywords: T cell-restricted intracellular antigen-1; TDP-43; amyotrophic lateral sclerosis; frontotemporal dementia; frontotemporal lobar degeneration; liquid-liquid phase separation; low-complexity domain; membrane-less organelle; stress granules.

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / pathology*
  • DNA-Binding Proteins / metabolism
  • Family Health
  • Female
  • Frontotemporal Dementia / genetics*
  • Frontotemporal Dementia / pathology*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism
  • Humans
  • Male
  • Microscopy, Confocal
  • Middle Aged
  • Mutation / genetics*
  • Poly(A)-Binding Proteins / genetics*
  • RNA-Binding Protein FUS / metabolism
  • Stress, Physiological / physiology
  • T-Cell Intracellular Antigen-1
  • Time Factors
  • Transfection

Substances

  • DNA-Binding Proteins
  • FUS protein, human
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Poly(A)-Binding Proteins
  • RNA-Binding Protein FUS
  • T-Cell Intracellular Antigen-1
  • TARDBP protein, human
  • TIA1 protein, human
  • Green Fluorescent Proteins