Mechanistic description
Symmetric dimethylation of arginine residues in the FUS RGG1/RGG2 domains by PRMT5/PRMT1 maintains FUS in a dynamic liquid phase-separated state by reducing inter-molecular beta-sheet propensity. ALS-linked mutations near the RGG domains reduce arginine methylation efficiency, shifting FUS toward an aggregation-prone unmethylated state. PRMT5 activator treatment in FUS-ALS iPSC motor neurons should restore arginine methylation stoichiometry and increase the concentration required for pathological aggregation by >3-fold.
Mechanism / pathway
- FUS
- Arginine methylation / RBP phase separation
- ALS
Evidence for (5)
ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes.
ALS-associated FUS mutation reshapes the RNA and protein composition of stress granules.
A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation.
M6A-dependent RNA condensation underlies FUS autoregulation and can be harnessed for ALS therapy development.
Pathogenesis of FUS-associated ALS and FTD: insights from rodent models.
Evidence against (2)
Evidence matrix
Supporting
- ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes. PMID:39167487 · 2024 · Cell Rep
- ALS-associated FUS mutation reshapes the RNA and protein composition of stress granules. PMID:39494508 · 2024 · Nucleic Acids Res
- A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. PMID:26317470 · 2015 · Cell
- M6A-dependent RNA condensation underlies FUS autoregulation and can be harnessed for ALS therapy development. PMID:40700505 · 2025 · Sci Adv
- Pathogenesis of FUS-associated ALS and FTD: insights from rodent models. PMID:27600654 · 2016 · Acta Neuropathol Commun
Contradicting
No contradicting evidence recorded.
Cite this hypothesis
Cite this hypothesis
etl-backfill (2026). Arginine Methylation Loss on FUS RGG Domains Drives Irreversible Phase Transiti…. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/897f3e4a-f96a-4a65-b3c8-61e20a1054da
@misc{scidex_hypothesis_897f3e4a,
title = {Arginine Methylation Loss on FUS RGG Domains Drives Irreversible Phase Transiti…},
author = {etl-backfill},
year = {2026},
howpublished = {SciDEX hypothesis},
url = {https://prism.scidex.ai/hypotheses/897f3e4a-f96a-4a65-b3c8-61e20a1054da},
note = {SciDEX artifact hypothesis:897f3e4a-f96a-4a65-b3c8-61e20a1054da}
}