Wittmer, Y.; Murray, D. T.

Mutations in the low complexity domains of RNA-binding proteins are associated with neurodegenerative disease pathology. The TIA1 RNA-binding protein harbors seven such mutations linked to a clinical cohort of ALS patients. The altered low complexity domain sequence increases the number of TIA1-rich stress granules in cultured cells, delays their disassembly, and is associated with increased fibril formation. Altered molecular motions and contacts in condensed states like stress granules that result in the formation of amyloid-like fibril states is commonly observed for RNA-binding biomolecular condensates. Here we focus on the influence of the ALS mutations on fibril formation of the TIA1 low complexity domain. Repetitive seeding preparations of the seven TIA1 protein mutants all yield amyloid-like fibrils based on transmission electron microscopy images and increased thioflavin T fluorescence. Analysis of solid state nuclear magnetic resonance spectra recorded on all seven mutant fibrils reveals distinct structural differences in the relative to wild-type fibrils. Our results shed light on how the mutations affect structural conformations accessible to the TIA1 low complexity domain.