Despite TARDBP mutations only accounting for about 3–5% of cases with familial ALS and less than 1% of those with idiopathic ALS, the TDP-43 protein is the major constituent of ubiquitinated cytoplasmic inclusions in the vast majority of people with ALS at postmortem, and in about 50% of people with frontotemporal dementia.29 The neuropathological features of TARDBP-ALS resemble those of TDP-43 pathology commonly detected in idiopathic patients with ALS or frontotemporal dementia (figure 1). Here, TARDBP is linked to amyotrophic lateral sclerosis.