Fig. 6: NUPR2 is the only differentially expressed gene between sporadic and C9-HRE FTD neurons and the neurons display altered nuclear morphologies and presence of micronuclei.

NUPR2, potentially related to the DNA damage pathway, is the only differentially expressed gene when comparing the C9-HRE and sporadic FTD neurons (A). Both sporadic (C9-) and C9-HRE-carrying FTD (C9+) neurons display nuclei, which are significantly rounder in shape as well as significantly smaller compared to healthy neuron nuclei, indicated by altered nuclear eccentricity (B), and a higher number of micronuclei (C). A representative image of a micronucleus next to the nucleus is shown (arrow). Kruskal-Wallis test followed by Dunn’s multiple comparisons test was used. n [Control] = 74; n [C9−] = 17; n [C9+] = 21. In addition, the distribution of larger and smaller sized nuclei is different in FTD neurons than that in control neurons (D–F). Representative images of control, C9-, and C9+ neurons treated with vehicle (upper panel) or 10 µM topotecan (lower panel). The neurons were stained with antibodies against MAP2 (red) and γH2A.X (green). Nuclei were stained with DAPI (blue) (G). Topotecan treatment significantly increases the number of γH2A.X-positive foci in the nuclei in all neurons, indicating increased DNA damage. At baseline, C9+ neurons display a slightly higher number of γH2A.X foci compared to control neurons, although this difference is not statistically significant (H–J). Kruskal-Wallis test followed by Dunn’s multiple comparisons test was used. n [Control] = 26–28; n [C9−] = 15–18; n [C9+] = 44–64. Statistically significant differences are shown as *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001.