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

Neuron | Aug 16, 2017

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.

Pubmed ID: 28817800 RIS Download

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

Data used in this publication

None found

Associated grants

  • Agency: NIA NIH HHS, Id: P30 AG013854
  • Agency: NINDS NIH HHS, Id: R35 NS097273
  • Agency: NIA NIH HHS, Id: R01 AG031581
  • Agency: NIA NIH HHS, Id: P50 AG016574
  • Agency: NINDS NIH HHS, Id: U54 NS092091
  • Agency: NINDS NIH HHS, Id: R35 NS097261
  • Agency: NINDS NIH HHS, Id: R01 NS076471
  • Agency: NCATS NIH HHS, Id: UL1 TR001422
  • Agency: Howard Hughes Medical Institute, Id: R35 NS097974
  • Agency: NINDS NIH HHS, Id: P50 NS072187
  • Agency: NINDS NIH HHS, Id: P01 NS084974
  • Agency: NINDS NIH HHS, Id: P30 AG019610
  • Agency: NIA NIH HHS, Id: R01 NS072248
  • Agency: NINDS NIH HHS, Id: R01 NS075764
  • Agency: NINDS NIH HHS, Id:

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