In ALS, TDP-43 is pathologically phosphorylated and C-terminally truncated in cytoplasmic aggregates.5 The toxicity may be partly loss and partly gain-of-function: insoluble aggregates inhibit TDP-43 function in transcriptional regulation, while cytoplasmic aggregates can lead to the dysregulation of proteostasis and sequester other aggregation prone proteins, causing further cytotoxicity and contributing to cell death.6 7. Here, TARDBP is linked to amyotrophic lateral sclerosis.