Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.
In: The Journal of clinical investigation, Jg. 130 (2020-11-02), Heft 11, S. 6080-6092
Online
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Zugriff:
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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Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.
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Autor/in / Beteiligte Person: | Prudencio, M ; Humphrey, J ; Pickles, S ; Brown, AL ; Hill, SE ; Kachergus, JM ; Shi, J ; Heckman, MG ; Spiegel, MR ; Cook, C ; Song, Y ; Yue, M ; Daughrity, LM ; Carlomagno, Y ; Jansen-West, K ; de Castro CF ; DeTure, M ; Koga, S ; Wang, YC ; Sivakumar, P ; Bodo, C ; Candalija, A ; Talbot, K ; Selvaraj, BT ; Burr, K ; Chandran, S ; Newcombe, J ; Lashley, T ; Hubbard, I ; Catalano, D ; Kim, D ; Propp, N ; Fennessey, S ; Fagegaltier, D ; Phatnani, H ; Secrier, M ; Fisher, EM ; Oskarsson, B ; van Blitterswijk M ; Rademakers, R ; Graff-Radford, NR ; Boeve, BF ; Knopman, DS ; Petersen, RC ; Josephs, KA ; Thompson, EA ; Raj, T ; Ward, M ; Dickson, DW ; Gendron, TF ; Fratta, P ; Petrucelli, L |
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Zeitschrift: | The Journal of clinical investigation, Jg. 130 (2020-11-02), Heft 11, S. 6080-6092 |
Veröffentlichung: | 1999- : Ann Arbor, MI : American Society for Clinical Investigation ; <i>Original Publication</i>: New Haven [etc.] American Society for Clinical Investigation., 2020 |
Medientyp: | academicJournal |
ISSN: | 1558-8238 (electronic) |
DOI: | 10.1172/JCI139741 |
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