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

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

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 1

Truncated STMN2 RNA is generated with loss of nuclear TDP-43.

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Truncated STMN2 RNA is generated with loss of nuclear TDP-43. Schematic ...
Schematic of TDP-43–regulated STMN2 splicing. When TDP-43 is present and functional, it binds to GU-rich sequences in the first intron of the STMN2 transcript and allows normal splicing of intron 1. Reduced TDP-43 binding to STMN2 RNA, from TDP-43 aggregation or depletion from the nucleus, leads to mis-splicing of STMN2 RNA, resulting in the inclusion of a novel exon encoded within intron 1 (termed exon 2a) and containing an alternative or cryptic polyadenylation site. The production of this alternative variant of STMN2, which lacks exons 2 through 5 (referred to as truncated STMN2), is at the expense of full-length STMN2, which is reduced upon TDP-43 downregulation.