The TDP-43 research project started as a CARD Challenge. TDP-43, a protein that regulates RNA splicing, stops functioning normally in patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). This results in abnormal splicing events that produce abnormal proteins and RNA portions called cryptic exons that may contribute to disease.
CARD and NINDS researchers are investigating whether these cryptic exons are present in induced pluripotent stem cells (iPSCs) that model neurodegenerative disease. Our researchers are also investigating whether proteins produced from these cryptic exons can be detected in the cerebrospinal fluids of FTD and ALS patients.
The goal is to identify the main cryptic exon and protein candidates in human cerebrospinal fluid (CSF) and plasma samples from the 65 candidate cryptic exons previously found in iPSC neurons (Brown et al., 2022). Researchers have already identified 25 proteins encoded by 12 genes that contain cryptic exons in patients with ALS (Seddighi et al., in review). These cryptic exons may ultimately enable the development of ultrasensitive clinical bioassays for ALS and FTD, and to monitor response to therapies during clinical trials.
Meet the TDP-43 Team
Related Publications and News:
- TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Brown et al. Nature. 2022. DOI: 10.1038/s41586-022-04436-3)
- Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD. Seddighi S, et al. bioRxiv. 2023. DOI: 10.1101/2023.01.23.525149