TY - JOUR
T1 - Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia
AU - NYGC ALS Consortium
AU - Prudencio, Mercedes
AU - Humphrey, Jack
AU - Pickles, Sarah
AU - Brown, Anna Leigh
AU - Hill, Sarah E.
AU - Kachergus, Jennifer M.
AU - Shi, J.
AU - Heckman, Michael G.
AU - Spiegel, Matthew R.
AU - Cook, Casey
AU - Song, Yuping
AU - Yue, Mei
AU - Daughrity, Lillian M.
AU - Carlomagno, Yari
AU - Jansen-West, Karen
AU - de Castro, Cristhoper Fernandez
AU - DeTure, Michael
AU - Koga, Shunsuke
AU - Wang, Ying Chih
AU - Sivakumar, Prasanth
AU - Bodo, Cristian
AU - Candalija, Ana
AU - Talbot, Kevin
AU - Selvaraj, Bhuvaneish T.
AU - Burr, Karen
AU - Chandran, Siddharthan
AU - Newcombe, Jia
AU - Lashley, Tammaryn
AU - Hubbard, Isabel
AU - Catalano, Demetra
AU - Kim, Duyang
AU - Propp, Nadia
AU - Fennessey, Samantha
AU - Fagegaltier, Delphine
AU - Phatnani, Hemali
AU - Secrier, Maria
AU - Fisher, Elizabeth M.C.
AU - Oskarsson, Björn
AU - van Blitterswijk, Marka
AU - Rademakers, Rosa
AU - Graff-Radford, Neil R.
AU - Boeve, Bradley F.
AU - Knopman, David S.
AU - Petersen, Ronald C.
AU - Josephs, Keith A.
AU - Aubrey Thompson, E.
AU - Raj, Towfique
AU - Dickson, Dennis W.
AU - Gendron, Tania F.
AU - Petrucelli, Leonard
N1 - Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/11/2
Y1 - 2020/11/2
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI139741
DO - 10.1172/JCI139741
M3 - Article
C2 - 32790644
AN - SCOPUS:85094978913
SN - 0021-9738
VL - 130
SP - 6080
EP - 6092
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -