Spinal muscular atrophy (SMA) is a devastating neurodegenerative disease caused by mutations in the SMN1 gene resulting in a decreased expression of the ubiquitous SMN protein. Given the crucial role of this SMN protein in the biogenesis of spliceosomal snRNPs (small nuclear ribonucleoproteins), the deficiency of this protein is correlated with numerous splicing alterations in patient cells, as well as in various tissues of SMA mouse models. The snRNPs involved in the minor spliceosome are particularly affected. Importantly, the splicing of several, but not all, U12-dependent introns was found to be affected in different SMA models.
In this study, French researchers investigated the molecular determinants involved in this differential splicing in the spinal cord of SMA mice. They showed that the branch point sequence (BPS) is a key element controlling the splicing efficiency of minor introns. Unexpectedly, splicing of multiple minor introns with suboptimal BPS is unaffected in SMA mice. Using in vitro splicing experiments and oligonucleotides targeting minor or major snRNAs, the authors showed for the first time that the splicing of these introns involves both minor and major machineries.
These results strongly suggest that in SMA mice, the splicing of a subset of minor introns is unaffected because major spliceosome components compensate for the loss of minor splicing activity.
