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Updated: Aug 28, 2025
12:57
Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
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ALS mutations in the TIA-1 prion-like domain trigger highly condensed pathogenic structures
Naotaka Sekiyama1, Kiyofumi Takaba2, Saori Maki-Yonekura2
1Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.
Summary
Mutations in the T cell intracellular antigen-1 (TIA-1) prion-like domain (PLD) impact stress granule formation. ALS-associated mutations enhance self-assembly, potentially leading to neurodegenerative disease pathogenicity.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- T cell intracellular antigen-1 (TIA-1) is crucial for stress granule (SG) formation through its prion-like domain (PLD).
- Specific mutations within the TIA-1 PLD are linked to neurodegenerative conditions like amyotrophic lateral sclerosis (ALS) and Welander distal myopathy (WDM).
- The precise impact of these mutations on PLD self-assembly dynamics and pathogenicity remains unclear.
Purpose of the Study:
- To elucidate the pathogenic structural changes induced by TIA-1 PLD mutations.
- To investigate how specific mutations associated with ALS and WDM affect the self-assembly properties of the TIA-1 PLD.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy to analyze PLD dynamic structures.
- Molecular dynamics (MD) simulations to model protein behavior.
- Three-dimensional electron crystallography for structural determination.
- Biochemical assays to assess self-assembly properties.
Main Results:
- NMR revealed that PLD's dynamic structure is influenced by physicochemical properties of amino acid sequences in five-residue units.
- The WDM-associated E384K mutation weakened the PLD's self-assembly (attenuated sticky properties).
- ALS-associated mutations P362L and A381T enhanced self-assembly, with P362L inducing β-sheet interactions and A381T promoting highly condensed assemblies.
Conclusions:
- The P362L and A381T mutations in TIA-1 PLD promote self-assembly, increasing the risk of irreversible amyloid fibril formation.
- Enhanced self-assembly and subsequent amyloidogenesis following phase-separated droplet formation are implicated as pathogenic mechanisms in ALS.
- Understanding these mutation-driven structural changes offers insights into the molecular basis of TIA-1-related neurodegenerative diseases.
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