Neurodegenerative diseases are characterized by the presence of protein inclusion bodies with a different protein content depending on the type of disease. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are no exceptions to this common theme. In most ALS and FTLD cases the predominant species of aggregated proteins are RNA-binding proteins (RBPs) (1). Yet the exact processes underlying this pathological aggregation remain unknown. In previous work we have shown that nuclear transport factors are modifiers of arginine-rich DPR toxicity (2, 3). These data suggest that DPRs could perturb the nucleocytoplasmic transport system, eventually resulting in cytoplasmic RBP mislocalization. We wondered whether DPRs also could play a direct role in the aggregation of these DPRs. Recent studies have shown that RBP aggregation is likely initiated from a liquid-like phase separated (LLPS) state. We now show that arginine-rich DPRs can undergo such phase transition themselves in vitro (4). This process is length- and dose-dependent, and is mediated by counterions or polyaromates. Moreover PR and GR are capable of affecting the phase separation and aggregation behavior of disease-relevant RBPs in vitro. Lastly, we found that PR and GR induce stress granule assembly in cells, and affect their dynamics and protein content. Our findings suggest that besides perturbing RBP subcellular localization, arginine-rich DPRs could also directly affect the phase separation and aggregation of RBPs in C9 ALS/FTLD pathology. In recent work we are further exploring the physical underpinnings of arginine-mediated phase separations and further characterizing the role of RNA in this process. We have recently shown that RNA can be an active mediator of phase separation of disordered arginine- rich domains (4). Yet there remain a lot of unanswered questions, and the general view is that RNA is mostly a passive bystander in protein phase separation. We have preliminary data that RNA sequence and structure are however major determinants of LLPS, and are further investigating this in vitro and in cells.