Decoding MAPT Exon 10 Mis-Splicing in FTDP-17: From Pathogenic Mechanisms and Experimental Models to Molecular Therapies

Abstract

Frontotemporal Dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is a rare, early-onset, autosomal-dominant neurodegenerative tauopathy caused by mutations in the Microtubule-Associated Protein Tau (MAPT) gene. A subset of these mutations selectively disrupts the normal alternative splicing of MAPT exon 10, altering the physiological ratio of 3-Repeat (3R) and 4-Repeat (4R) tau isoforms; this imbalance, driving pathological tau aggregation and progressive neurodegeneration, is a pathogenic hallmark of FTDP-17. This review explores the molecular mechanisms regulating exon 10 splicing, focusing on how exonic and intronic splicing mutations destabilise mRNA structures or alter splicing factor binding, and discusses how these changes can cause disease symptoms in experimental models. It describes different research methods for studying splicing issues, including minigene reporters, cell lines, human induced pluripotent stem cell (iPSC)-derived neurons, brain organoids and mouse models that naturally express only 4R tau. It also covers potential therapeutic approaches applicable to restoring the normal 3R/4R tau ratio. These include Antisense Oligonucleotides (ASOs), RNA interference (siRNA), Small-Molecule Splicing modulators (SMCs), Spliceosome-Mediated RNA trans-splicing (SMaRT), CRISPR-based transcript engineering, genome editing and RNA stem-loop binders. Additionally, the review highlights recent Phase 2 trial results, including the Diranersen (BIIB080) tau-lowering ASO, the development of MAPT-targeted RNA therapies, new tau-PET and plasma p-tau biomarkers, and innovative strategies to deliver CNS treatments, including non-invasive approaches. By integrating advances in RNA biology, disease modelling and targeted therapies, the review outlines potential future strategies for treating FTDP-17 and other tau-related disorders.