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.
Curated pathway from expert analysis
flowchart TD
A["FUS RGG1 RGG2 Domains<br/>RNA-Binding Protein in Motor Neurons"]
B["PRMT1 and PRMT5 Activity<br/>Symmetric Dimethylarginine on RGG Repeats"]
C["Dynamic Liquid Phase Separation<br/>Inter-molecular Beta-Sheet Propensity Reduced"]
D["ALS-Linked FUS Mutations<br/>Near RGG Domains"]
E["Reduced Arginine Methylation Efficiency<br/>Unmethylated FUS Accumulates"]
F["Increased Beta-Sheet Propensity<br/>Aggregation-Prone Confirmation"]
G["Insoluble FUS Amyloid Aggregates<br/>ALS FTD Pathology"]
H["PRMT5 Activator Treatment<br/>Restores Methylation Stoichiometry"]
A --> B
B --> C
D --> E
E --> F
F --> G
H -.->|"3-fold aggregation threshold increase"| B
style D fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for FUS.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.