(A) Strategy for labeling native TDP43 in human iPSC-derived neurons using CRISPR/Cas9. Dendra2 (D2, green) was inserted 3′ relative to the TARDBP start codon (green arrow) or 5′ relative to the conventional stop codon (red arrow), enabling fluorescent labeling of the TDP43 N- or C-terminus, respectively. In iNeurons, N-terminally tagged TDP43 (B, D2-TDP43) appeared both nuclear and cytoplasmic in distribution, while C-terminally tagged TDP43 (C, TDP43-D2) was primarily nuclear. (D) Density plot depicting the fluorescence intensity of D2-TDP43 upon application of vehicle (n = 158), TEA (n = 250), or TTX (n = 221). (E) Density plot depicting the fluorescence intensity of TDP43-D2 with addition of vehicle (n = 96), TEA (n = 145), or TTX (n = 98). In D and E, vertical lines indicate individual neurons from 2 replicates. **P < 0.01, ****P < 0.0001 by Kolmogorov-Smirnov test. Scale bars: 20 μm (B and C).