Expression of sense and antisense expanded C9 transcript RNA and dipeptide repeat (DPR) proteins affect a wide array of downstream cellular pathways including ER stress, nucleocytoplasmic defects, altered stress granule dynamics, autophagy dysfunction, translational defects, proteasome inhibition, RAN translation, nucleolar stress, RNA foci formation. Different therapeutic approaches (green boxes) target the C9 RNAs and RAN DPRs directly as well as the downstream pathways. Additionally, external factors, such as patient lifestyle, stress, comorbid diseases and environmental factors (bottom red bar) can influence cellular events with exercise and lifestyle changes offering mixed therapeutic potential. Some content modified from Servier Medical Art (smart.servier.com) under creative common license.