Fig. 4: Loss of TDP-43 binding to the 3′ UTR of NPTX2 leads to its aberrant accumulation in brains of patients with TDP-43 proteinopathy.
From: A model of human neural networks reveals NPTX2 pathology in ALS and FTLD
a, Gene expression (in CPM (counts per million)) of the top 10 marker genes that are upregulated in cluster 12 in matched TDP-43-negative and TDP-43-positive neuronal nuclei from patients with FTLD–ALS38 (subject numbers match those in ref. 38). b, Top, ___location of iCLIP crosslink sites in NPTX2 in control (green) and FTLD patient (red) human brains13. Bottom, magnified view of iCLIP crosslinks and GUGU repeats in the NPTX2 3′ UTR. c,d, Dual luminescence assay showed similar behaviour of TARDBP and NPTX2 3′ UTR reporters upon TDP-43 knockdown (c) and TDP-43–HA overexpression (d). Pairs analysed by Mann–Whitney U test. Different shades of grey indicate independent experiments. n = 14 independently treated wells over 3 experiments. Data shown are mean ± s.d. Two-tailed P values. Control (Ctrl) shRNA versus TARDBP shRNA for both TARDBP 3′ UTR and NPTX2 3′ UTR, P < 0.0001; TDP-43 OFF versus ON for both TARDBP 3′ UTR and NPTX2 3′ UTR, P < 0.0001. e–j, Immunofluorescence of human brain sections: FTLD-TDP-A (e) or FTLD-TDP-C (f) hippocampus, ALS primary motor cortex (g), and FTLD with FUS pathology (FTLD-FUS) (h), FTLD with tau pathology (FTLD-tau) (i) or Alzheimer’s disease (j) hippocampus, demonstrating inclusion-like NPTX2 signal only in MAP2-positive neurons containing aggregates composed of TDP-43p403/404 but not FUS or phosphorylated tau (taup202/205). Immunofluorescence was repeated four (FTLD-TDP-A and FTLD-TDP-C) or two times (FTLD-FUS, FTLD-tau, Alzheimer’s disease and ALS). Scale bars: 10 µm (e,f,h–j), 30 µm (g).
