Neuron
Volume 95, Issue 4, 16 August 2017, Pages 808-816.e9
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TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics

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Highlights

  • Mutations affecting the low-complexity domain of TIA1 cause ALS and ALS-FTD

  • ALS-linked TIA1 mutations share a neuropathological TDP-43 signature

  • TIA1 mutations promote phase separation and impair stress granule dynamics

  • TDP-43 recruited to poorly dynamic stress granules becomes immobile and insoluble

Summary

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

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

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These authors contributed equally

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