ALS-associated exitron splicing produces UBQLN2 isoforms with distinct properties

A study has unveiled a novel mechanism in X-linked amyotrophic lateral sclerosis (ALS) that involves alternative splicing of the Ubiquilin 2 (UBQLN2) gene. This gene is expressed in a single exon, yet its mRNA undergoes splicing through a cryptic exonic intron, or "exitron," which spans the 5 untranslated region and the 5 end of the coding sequence.

This splicing event generates a spliced UBQLN2 (UBQLN2-Sp) transcript that can be translated from codon M243, resulting in an N-terminally truncated UBQLN2 isoform (UBQLN2-M243). This truncated form exhibits reduced stability, diminished targeting by the proteasome, and altered aggregation behavior following the introduction of ALS mutations.

The RNA-binding proteins SRSF1 and PTBP1 regulate UBQLN2 splicing by binding to splice donor-proximal motifs, while TDP-43 acts as an indirect splicing repressor. Importantly, UBQLN2 splicing was found to be elevated in the medial motor cortex of male ALS patients, and inversely correlated with UBQLN2 gene expression. This suggests that alternative splicing plays a crucial role in regulating UBQLN2 gene dosage and function, potentially impacting UBQLN2-ALS proteinopathy.