OGT regulates RNA-binding protein nucleocytoplasmic partitioning, but this fails in amyotrophic lateral sclerosis.

Authors

Yiran Wang, Lisa Fournier, Benjamin Wymann, Kevin Talbot, Raphaëlle Luisier, Rickie Patani

Published in

iScience. Volume 29. Issue 11. Pages 117807. Nov 20, 2026. Epub Oct 08, 2026.

Abstract

O-linked N-acetylglucosamine transferase (OGT) catalyzes the O-linked β-N-acetylglucosamine (O-GlcNAc) modification to proteins and has been implicated in a range of diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and currently incurable neurodegenerative disorder. However, the precise mechanisms by which OGT influences ALS pathogenesis remain largely unresolved. In this study, we used human-induced pluripotent stem cell (hiPSC)-derived spinal motor neurons (hiPSC-MNs), the principal cell type that undergoes degeneration in ALS, to systematically reveal that OGT-related mechanisms regulate RNA-binding protein (RBP) nucleocytoplasmic compartmentalization. Using a combination of antisense oligonucleotide (ASO) technology and small molecular pharmacology, we reveal two distinct regulatory mechanisms of RBP compartmentalization, including by intron-retaining transcript-mediated sequestration and O-linked N-acetylglucosaminylation (O-GlcNAcylation)-mediated nuclear transport. We finally examine the tractability of manipulating OGT activity in the ALS context but demonstrate that the OGT-related mechanisms governing RBP localization in healthy hiPSC-MNs are impaired in the context of ALS-causing VCP and TARDBP mutations.

PMID:
42894639
Bibliographic data and abstract were imported from PubMed on 19 Oct 2026.

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