These data, as well as early-onset DPR inclusions in animal models and their inherent toxicity, illustrate the importance of studying the accumulation of brain DPRs in a time- and cell-dependent fashion and may explain why some poly-DPR pathologies are rare in post-mortem brain tissues from C9orf72-ALS/FTD patients, which reflect the end stage of disease and may likely have neuronal death obscuring the mechanisms through which DPRs are causing toxicity. Here, C9orf72 is linked to amyotrophic lateral sclerosis.