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Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is caused by mutations in theMAPTgene, encoding the tau protein that accumulates in intraneuronal lesions in a number of neurodegenerative diseases. Several FTDP-17 mutations affect alternative splicing and result in excess exon 10 (E10) inclusion in tau mRNA. RNA reprogramming using spliceosome-mediated RNAtrans-splicing (SMaRT) could be a method of choice to correct aberrant E10 splicing resulting from FTDP-17 mutations. SMaRT creates a hybrid mRNA through atrans-splicing reaction between an endogenous target pre-mRNA and a pre-trans-splicing RNA molecule (PTM). However, FTDP-17 mutations affect the strength ofcis-splicing elements and could favorcis-splicing overtrans-splicing. Excess E10 inclusion in FTDP-17 can be caused by intronic mutations destabilizing a stem-loop protecting the 5′ splice site at the E10/intron 10 junction. COS cells transfected with a minigene containing the intronic +14 mutation produce exclusively E10+RNA. Generation of E10−RNA was restored after co-transfection with a PTM designed to exclude E10. Similar results were obtained with a target containing the exonic N279K mutation which strengthens a splicing enhancer within E10. Conversely, increase or decrease in E10 content was achieved bytrans-splicing from a target carrying the Δ280K mutation, which weakens the same splicing enhancer. Thus E10 inclusion can be modulated bytrans-splicing irrespective of the strength of thecis-splicing elements affected by FTDP-17 mutations. In conclusion, RNAtrans-splicing could provide the basis of therapeutic strategies for impaired alternative splicing caused by pathogenic mutations incis-acting splicing elements.

human molecular genetics

Correction of tau mis-splicing caused by FTDP-17               MAPT               mutations by spliceosome-mediated RNA               trans-              splicing