ALS-associated exitron splicing produces UBQLN2 isoforms with distinct properties
- 1University of Wisconsin-Madison
Abstract
X-linked amyotrophic lateral sclerosis (ALS) implicated Ubiquilin 2 (UBQLN2) is expressed from a single exon. Here, we show that human UBQLN2 mRNA is alternatively spliced by virtue of a cryptic exonic intron (exitron) spanning the 5' untranslated region and the 5' end of UBQLN2 coding sequence. Splice-out of this exitron generates a spliced UBQLN2 (UBQLN2-Sp) transcript that is translated from codon M243 to produce an N-terminally truncated UBQLN2 isoform (UBQLN2-M243) with reduced stability, diminished proteasome targeting, and altered aggregation behavior following the introduction of ALS mutations. The RNA-binding proteins SRSF1 and PTBP1 control UBQLN2 splicing through binding to splice donor-proximal motifs, while TDP-43 was implicated as an indirect splicing repressor. UBQLN2 splicing was elevated and inversely correlated with UBQLN2 gene expression in the medial motor cortex of male ALS patients. These findings suggest that alternative splicing regulates UBQLN2 gene dosage and function, which may impact UBQLN2-ALS proteinopathy.
Related
- Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle
- Subcellular Localization and Cell Cycle-Associated Expression of Human dUTPase Isoforms
- Two closely related RNA helicases, UAP56 and URH49, couple mRNA splicing and export pathways with their distinct complexes
- Beyond chaperoning: HSPA8 modulates alternative splicing of PPP2R2D to drive apoptotic evasion and macrophage-associated immune microenvironment remodeling in triple-negative breast cancer.
- Multi-omics analysis identifies ANXA2-associated transcriptomic and splicing networks in osteoblast proliferation and apoptosis
BibTeX
@misc{koo2026alsassociated,
title = {{ALS-associated exitron splicing produces UBQLN2 isoforms with distinct properties}},
author = {A. S. H. Koo and J. Zhou and N. M. Mendez-Albelo and Y. Wei and W. Xu and X. Zhao and C. N. Dewey and R. S. Tibbetts},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.750250},
url = {https://www.biorxiv.org/content/10.64898/2026.09.08.750250v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - ALS-associated exitron splicing produces UBQLN2 isoforms with distinct properties
AU - A. S. H. Koo
AU - J. Zhou
AU - N. M. Mendez-Albelo
AU - Y. Wei
AU - W. Xu
AU - X. Zhao
AU - C. N. Dewey
AU - R. S. Tibbetts
PY - 2026
DA - 2026/09/08
PB - bioRxiv
DO - 10.64898/2026.09.08.750250
UR - https://www.biorxiv.org/content/10.64898/2026.09.08.750250v1
AB - X-linked amyotrophic lateral sclerosis (ALS) implicated Ubiquilin 2 (UBQLN2) is expressed from a single exon. Here, we show that human UBQLN2 mRNA is alternatively spliced by virtue of a cryptic exonic intron (exitron) spanning the 5' untranslated region and the 5' end of UBQLN2 coding sequence. Splice-out of this exitron generates a spliced UBQLN2 (UBQLN2-Sp) transcript that is translated from codon M243 to produce an N-terminally truncated UBQLN2 isoform (UBQLN2-M243) with reduced stability, diminished proteasome targeting, and altered aggregation behavior following the introduction of ALS mutations. The RNA-binding proteins SRSF1 and PTBP1 control UBQLN2 splicing through binding to splice donor-proximal motifs, while TDP-43 was implicated as an indirect splicing repressor. UBQLN2 splicing was elevated and inversely correlated with UBQLN2 gene expression in the medial motor cortex of male ALS patients. These findings suggest that alternative splicing regulates UBQLN2 gene dosage and function, which may impact UBQLN2-ALS proteinopathy.
ER -