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Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia
Mercedes Prudencio, … , Pietro Fratta, Leonard Petrucelli
Mercedes Prudencio, … , Pietro Fratta, Leonard Petrucelli
Published August 13, 2020
Citation Information: J Clin Invest. 2020;130(11):e139741. https://doi.org/10.1172/JCI139741.
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Research Article Neuroscience Article has an altmetric score of 30

Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia

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Abstract

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell–derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.

Authors

Mercedes Prudencio, Jack Humphrey, Sarah Pickles, Anna-Leigh Brown, Sarah E. Hill, Jennifer M. Kachergus, J. Shi, Michael G. Heckman, Matthew R. Spiegel, Casey Cook, Yuping Song, Mei Yue, Lillian M. Daughrity, Yari Carlomagno, Karen Jansen-West, Cristhoper Fernandez de Castro, Michael DeTure, Shunsuke Koga, Ying-Chih Wang, Prasanth Sivakumar, Cristian Bodo, Ana Candalija, Kevin Talbot, Bhuvaneish T. Selvaraj, Karen Burr, Siddharthan Chandran, Jia Newcombe, Tammaryn Lashley, Isabel Hubbard, Demetra Catalano, Duyang Kim, Nadia Propp, Samantha Fennessey, NYGC ALS Consortium, Delphine Fagegaltier, Hemali Phatnani, Maria Secrier, Elizabeth M.C. Fisher, Björn Oskarsson, Marka van Blitterswijk, Rosa Rademakers, Neil R. Graff-Radford, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Keith A. Josephs, E. Aubrey Thompson, Towfique Raj, Michael Ward, Dennis W. Dickson, Tania F. Gendron, Pietro Fratta, Leonard Petrucelli

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Figure 2

Truncated STMN2 RNA is elevated in iPSC-derived neurons with reduced levels of TDP-43.

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Truncated STMN2 RNA is elevated in iPSC-derived neurons with reduced lev...
(A–C) iPSC-derived cortical neurons constitutively expressing CRISPR inactivation machinery (data set labeled “a”) were transduced with a lentivirus expressing a sgRNA against TARDBP (TDP-43 KD) or a control sgRNA (Controls) and subjected to analysis by qRT-PCR (n = 3 TDP-43 KD, n = 3 controls) and/or RNA-Seq (n = 3 TDP-43 KD, n = 4 controls). The graphs show a decrease in TARDBP transcripts (A), a reduction of the full-length STMN2 transcript (B), and an increase in the truncated STMN2 transcript (C) upon TDP-43 depletion. (D) Detection of STMN2 cryptic exon 2a inclusion expressed as PSI by RNA-Seq in various iPSC-derived neurons: iPSC-derived cortical neurons (data set labeled “a”) described above and performed in this study; iPSC-derived motor neurons treated with TARDBP siRNA (TDP-43 KD) or control siRNA (controls) from Klim et al. (data set labeled “b”) (n = 6 TDP-43 KD, n = 11 controls) (7); iPSC-derived motor neurons from patients with TARDBP mutations (TDP-43 mut.) or controls from 2 independent groups in Edinburgh (data set labeled “c”) (n = 7 TDP-43 KD, n = 4 controls) and Oxford (data set labeled “d”) (n = 10 TDP-43 KD, n = 4 controls) (72). Data are presented as the mean ± SEM and were normalized to the control groups in A and B (set to 100%). *P < 0.05, ***P < 0.005, and ****P < 0.001, by Student’s t test (A–C) or 1-way ANOVA (D). (E) Representative images of iPSC-derived motor neurons from patients with TARDBP mutations and control subjects from a group in Oxford (data set labeled “d” in Figure 1D) showed similar nuclear-cytoplasmic distribution of TDP-43 (green) on day 30 of differentiation (DAPI in blue, choline acetyltransferase [ChAT] in white). Scale bar: 10 μm. All panels of Figure 2E are reshown in Supplemental Figure 3A. Additional data associated with this figure can also be found in Supplemental Figure 3. See also the complete unedited blots in the supplemental material.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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