Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia
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. Overall design: Oct 19, 2020 release of postmortem RNASeq data from 1606 samples in the NYGC ALS Consortium; metadata is available upon request at ALSdata@nygenome.org. Differential STMN2 gene expression (processed count data) and splicing analyses of Amyotrophic Lateral Sclerosis (ALS), ALS-FTD and Control postmortem samples in Prudencio et al. 2020 were performed on samples from this release and prior NYGC ALS Consortium releases. contributor: NYGC ALS Consortium contributor: The Target ALS Human Postmortem Tissue Core contributor: Jack Humphrey (processed count data)