Humphrey Lab - Truncated stathmin-2 is a marker of TDP-43 pathology in

Journal article

M. Prudencio, J. Humphrey, Sarah R Pickles, Anna L. Brown, Sarah E. Hill, J. Kachergus, Ji Shi, M. Heckman, Matthew R. Spiegel, C. Cook, Yuping Song, Mei Yue, Lillian M. Daughrity, Y. Carlomagno, Karen R. Jansen-West, Cristhoper H. Fernandez De Castro, M. DeTure, S. Koga, Ying-Chih Wang, P. Sivakumar, C. Bodo, A. Candalija, K. Talbot, B. Selvaraj, K. Burr, S. Chandran, J. Newcombe, T. Lashley, I. Hubbard, Demetra Catalano, Duyang Kim, Nadia A. Propp, S. Fennessey, D. Fagegaltier, H. Phatnani, M. Secrier, E. Fisher, B. Oskarsson, M. van Blitterswijk, R. Rademakers, N. Graff-Radford, B. Boeve, D. Knopman, R. Petersen, K. Josephs, E. Thompson, T. Raj, Michael E. Ward, Dennis W. Dickson, T. Gendron, P. Fratta, L. Petrucelli
Journal of Clinical Investigation, 2020

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APA Click to copy
Prudencio, M., Humphrey, J., Pickles, S. R., Brown, A. L., Hill, S. E., Kachergus, J., … Petrucelli, L. (2020). Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia. Journal of Clinical Investigation.

Chicago/Turabian Click to copy
Prudencio, M., J. Humphrey, Sarah R Pickles, Anna L. Brown, Sarah E. Hill, J. Kachergus, Ji Shi, et al. “Truncated Stathmin-2 Is a Marker of TDP-43 Pathology in Frontotemporal Dementia.” Journal of Clinical Investigation (2020).

MLA Click to copy
Prudencio, M., et al. “Truncated Stathmin-2 Is a Marker of TDP-43 Pathology in Frontotemporal Dementia.” Journal of Clinical Investigation, 2020.

BibTeX Click to copy

@article{m2020a,
  title = {Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.},
  year = {2020},
  journal = {Journal of Clinical Investigation},
  author = {Prudencio, M. and Humphrey, J. and Pickles, Sarah R and Brown, Anna L. and Hill, Sarah E. and Kachergus, J. and Shi, Ji and Heckman, M. and Spiegel, Matthew R. and Cook, C. and Song, Yuping and Yue, Mei and Daughrity, Lillian M. and Carlomagno, Y. and Jansen-West, Karen R. and Castro, Cristhoper H. Fernandez De and DeTure, M. and Koga, S. and Wang, Ying-Chih and Sivakumar, P. and Bodo, C. and Candalija, A. and Talbot, K. and Selvaraj, B. and Burr, K. and Chandran, S. and Newcombe, J. and Lashley, T. and Hubbard, I. and Catalano, Demetra and Kim, Duyang and Propp, Nadia A. and Fennessey, S. and Fagegaltier, D. and Phatnani, H. and Secrier, M. and Fisher, E. and Oskarsson, B. and van Blitterswijk, M. and Rademakers, R. and Graff-Radford, N. and Boeve, B. and Knopman, D. and Petersen, R. and Josephs, K. and Thompson, E. and Raj, T. and Ward, Michael E. and Dickson, Dennis W. and Gendron, T. and Fratta, P. and Petrucelli, L.}
}

Abstract

No treatment for frontotemporal dementia (FTD), the second most common early-onset dementia, is available but therapeutics are being investigated to target the two main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hamstrung 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 reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human iPSC-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 sub-types marked by TDP-43 inclusions. Lastly, we validated that truncated STMN2 RNA is elevated in the frontal cortex of a cohort of FTLD-TDP cases but not in controls or cases with progressive supranuclear palsy (PSP), a type of FTLD-tau. Further, in 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.