Recognition that loss of normal TDP-43 function may also, or instead, be pathogenic in ALS was based upon the observation that TDP-43, both in human ALS tissue and transgenic animal models harboring TDP-43 inclusions, is cleared from its normal location in the nucleus (Mitra et al., 2019; Braak and Del Tredici, 2018; Walker et al., 2015; Braak et al., 2017). This evidence concerns the gene TARDBP and amyotrophic lateral sclerosis.