Protein-RNA condensates: Complementary or competing interactions in ALS progression?

Abstract

Membraneless organelles within cells provide organization of the intracellular environment through the process of liquid liquid phase separation (LLPS). The fused in sarcoma (FUS) protein is an RNA binding protein that undergoes LLPS with RNA as part of normal activity in healthy cells. PolyPR and polyGR, dipeptide repeat proteins (DPRs) caused by C9orf72 repeat expansion disorders, have been shown to promote protein aggregation of RNA binding proteins, including FUS. This aggregation contributes to the progression of ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia), which have ineffective treatments and no cure. The pathway towards protein aggregation, and away from stable condensates, is poorly understood, but has been linked to changes in condensate behavior induced by the addition of DPRs. Here we investigate the effect of DPR and RNA on the stability of FUS condensates through molecular dynamics simulations.