Detection of cryptic exons (splicing differences) in TDP-43 as biomarkers for frontotemporal dementia and Alzheimer's disease

National Institute On Aging

Investigators

Abstract

After successfully addressing goals 1 and 2, we have been working towards identifying the main cryptic exon candidates in human CSF and plasma samples. Over the last year, we obtained more than 200 samples of human CSF from patients with ALS, progressive supranuclear palsy (PSP), and control cases to determine if TDP-43 cryptic exons are present in diseased but not control patients. Our efforts using patient CSF have been critical in confirming and expanding on our findings in iPSC neurons. We detected 65 candidate cryptic exons and performed two-dimensional targeted mass spectrometry to identify lead cryptic peptide candidates. The manuscript detailing these experiments is currently in revision, and a pre-print on our findings has been deposited to Biorxiv. We are now attempting to utilize the cryptic peptides and cryptic exons identified in our previous study to develop peptide and RNA-based biomarkers and ultra-sensitive bioassays for clinical application. We are currently working with industry partner BioMarin, as well as Dr. Pietro Fratta from University College London, and Dr. David Walt from Harvard University to further investigate the creation of biomarkers. Brown, Anna-Leigh, et al. "TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A." Nature 603.7899 (2022): 131-137. https://doi.org/10.1038/s41586-022-04436-3 PubMed ID 35197628 PubMed Central ID PMC8891020 Seddighi, Sahba, et al. Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD (2023, submitted). Preprint via bioRxiv https://doi.org/10.1101/2023.01.23.525149