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.
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.