Analysis of the splicing landscape of the frontal cortex in FTLD-TDP reveals subtype specific patterns and cryptic splicing
Summary
Dysregulation of TDP-43 as seen in TDP-43 proteinopathies leads to specific RNA splicing dysfunction. While discovery studies have explored novel TDP-43-driven splicing events in induced pluripotent stem cell (iPSC)-derived neurons and TDP-43 negative neuronal nuclei, transcriptome-wide investigations in frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP) brains remain unexplored. Such studies hold promise for identifying widespread novel and relevant splicing alterations in FTLD-TDP patient brains. We conducted the largest differential splicing analysis (DSA) using bulk short-read RNAseq data from frontal cortex (FCX) tissue of 127 FTLD-TDP (A, B, C, GRN and C9orf72 carriers) and 22 control subjects (Mayo Clinic Brain Bank), using Leafcutter. In addition, long-read bulk cDNA sequencing data were generated from FCX of 9 FTLD-TDP and 7 controls and human TARDBP wildtype and knock-down iPSC-derived neurons. Publicly available RNAseq data (MayoRNAseq, MSBB and ROSMAP studies) from Alzheimer's disease patients (AD) was also analyzed. Our DSA revealed extensive splicing alterations in FTLD-TDP patients with 1881 differentially spliced events, in 892 unique genes. When evaluating differences between FTLD-TDP subtypes, we found that C9orf72 repeat expansion carriers carried the most splicing alterations after accounting for differences in cell-type proportions. Focusing on cryptic splicing events, we identified STMN2 and ARHGAP32 as genes with the most abundant and differentially expressed cryptic exons between FTLD-TDP patients and controls in the brain, and we uncovered a set of 17 cryptic events consistently observed across studies, highlighting their potential relevance as biomarkers for TDP-43 proteinopathies. We also identified 16 cryptic events shared between FTLD-TDP and AD brains, suggesting potential common splicing dysregulation pathways in neurodegenerative diseases. Overall, this study provides a comprehensive map of splicing alterations in FTLD-TDP brains, revealing subtype-specific differences and identifying promising candidates for biomarker development and potential common pathogenic mechanisms between FTLD-TDP and AD. © 2025. The Author(s).
| Authors | Faura J, Heeman B, Pottier C, Baker MC, DeJesus-Hernandez M, Küçükali F, Heiß L, Wynants S, Van den Broeck M, De Rijk P, De Pooter T, Joris G, Finch NA, Asmann Y, Strazisar M, Murray ME, Petrucelli L, Oskarsson B, Sleegers K, Josephs KA, Nguyen AT, Reichard RR, Petersen RC, Boeve BF, Graff-Radford NR, Dickson DW, van Blitterswijk M, Rademakers R |
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| Journal | Acta neuropathologica |
| Publication Date | 2025 Jun 6;149(1):59 |
| PubMed | 40478310 |
| PubMed Central | PMC12143990 |
| DOI | 10.1007/s00401-025-02901-7 |