Cellular stress, protein aggregation, and cytoskeletal dysfunction initiated by disease-causing mutations or by environmental factors such as ageing, all have been independently shown to initiate a cascade of events that culminate in the disruption of normal NCT of proteins and RNAs. However, these pathways are not independent of each other, and each one can induce additional damage by further promoting protein aggregation, cytoskeletal disruption, and cellular stress. We hypothesize that an insult in any of these pathways can result in triggering this vicious cycle, resulting in NCT defects and neuronal death in ALS/FTD.