1. Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia
- Author
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Prasanth Sivakumar, Jack Humphrey, Keith A. Josephs, Mercedes Prudencio, E. Aubrey Thompson, Kevin Talbot, Bjorn Oskarsson, Hemali Phatnani, Leonard Petrucelli, Ana Candalija, David S. Knopman, Pietro Fratta, Casey Cook, Yari Carlomagno, Cristhoper H. Fernandez De Castro, Duyang Kim, Neil Graff-Radford, Maria Secrier, Siddharthan Chandran, Mei Yue, Anna-Leigh Brown, Sarah E. Hill, Bhuvaneish T. Selvaraj, Michael G. Heckman, Cristian Bodo, Karen Jansen-West, Michael E. Ward, Demetra Catalano, Samantha Fennessey, Elizabeth M. C. Fisher, Michael DeTure, Ronald C. Petersen, Dennis W. Dickson, Jia Newcombe, Isabel Hubbard, Delphine Fagegaltier, Tania F. Gendron, Ying-Chih Wang, Karen Burr, Lillian M. Daughrity, Tammaryn Lashley, J. Shi, Yuping Song, Jennifer M. Kachergus, Matthew R. Spiegel, Rosa Rademakers, Marka van Blitterswijk, Shunsuke Koga, Bradley F. Boeve, Sarah R. Pickles, Nadia Propp, and Towfique Raj
- Subjects
Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Induced Pluripotent Stem Cells ,Stathmin ,Disease ,TARDBP ,Progressive supranuclear palsy ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,Humans ,Medicine ,Dementia ,biology ,business.industry ,nutritional and metabolic diseases ,RNA ,General Medicine ,Human brain ,Middle Aged ,medicine.disease ,Frontal Lobe ,nervous system diseases ,DNA-Binding Proteins ,030104 developmental biology ,medicine.anatomical_structure ,Frontotemporal Dementia ,030220 oncology & carcinogenesis ,Mutation ,Commentary ,biology.protein ,Female ,business ,Biomarkers ,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.
- Published
- 2020