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.
The Journal of clinical investigation
Digital Object Identifier (DOI)
Prudencio, Mercedes; Humphrey, Jack; Pickles, Sarah; Brown, Anna-Leigh; Hill, Sarah E; Kachergus, Jennifer M; Shi, J; Heckman, Michael G; Spiegel, Matthew R; Cook, Casey; Song, Yuping; Yue, Mei; Daughrity, Lillian M; Carlomagno, Yari; Jansen-West, Karen; de Castro, Cristhoper Fernandez; DeTure, Michael; Koga, Shunsuke; Wang, Ying-Chih; Sivakumar, Prasanth; Bodo, Cristian; Candalija, Ana; Talbot, Kevin; Selvaraj, Bhuvaneish T; Burr, Karen; Chandran, Siddharthan; Newcombe, Jia; Lashley, Tammaryn; Hubbard, Isabel; Catalano, Demetra; Kim, Duyang; Propp, Nadia; Fennessey, Samantha; Fagegaltier, Delphine; Phatnani, Hemali; Secrier, Maria; Fisher, Elizabeth Mc; Oskarsson, Björn; van Blitterswijk, Marka; Rademakers, Rosa; Graff-Radford, Neil R; Boeve, Bradley F; Knopman, David S; Petersen, Ronald C; Josephs, Keith A; Thompson, E Aubrey; Raj, Towfique; Ward, Michael; Dickson, Dennis W; Gendron, Tania F; Fratta, Pietro; Petrucelli, Leonard; and Bowser, Robert, "Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia." (2020). Neurobiology. 727.