The effect of dipeptide repeat proteins on FUS/TDP43-RNA condensation in C9orf72 ALS/FTD

Condensation of RNA binding proteins (RBPs) with RNA is essential for cellular function. The most common familial cause of the diseases ALS and FTD are C9orf72 repeat expansion disorders that produce dipeptide repeat proteins (DPRs). We explore the hypothesis that DPRs disrupt the native condensation behaviour of RBPs and RNA through molecular interactions resulting in toxicity. FUS and TDP43 are two RBPs known to be affected in ALS/FTD. We use our previously developed 1-bead-per-amino acid and a newly developed 3-bead-per-nucleic acid molecular dynamics model to explore ternary phase diagrams of FUS/TDP43-RNA-DPR systems. We show that the most toxic arginine containing DPRs (R-DPRs), can disrupt the RBP condensates through cation- π interactions, and can strongly sequester RNA through electrostatic interactions. The native droplet morphologies are already modified at small additions of R-DPRs leading to non-native FUS/TDP43-encapsulated condensates with a marbled RNA/DPR core.