Pathophysiological interplay between O-GlcNAc transferase and the Machado-Joseph disease protein ataxin-3

Priscila Pereira Sena, Jonasz J. Weber, Maxinne Watchon, Katherine J. Robinson, Zinah Wassouf, Stefan Hauser, Jacob Helm, Mahkameh Abeditashi, Jana Schmidt, Jeannette Hubener-Schmid, Ludger Schols, Angela S. Laird, Olaf Riess, Thorsten Schmidt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


Aberrant O-GlcNAcylation, a protein posttranslational modification defined by the O-linked attachment of the monosaccharide N-acetylglucosamine (O-GlcNAc), has been implicated in neurodegenerative diseases. However, although many neuronal proteins are substrates for O-GlcNAcylation, this process has not been extensively investigated in polyglutamine disorders. We aimed to evaluate the enzyme O-GlcNAc transferase (OGT), which attaches O-GlcNAc to target proteins, in Machado-Joseph disease (MJD). MJD is a neurodegenerative condition characterized by ataxia and caused by the expansion of a polyglutamine stretch within the deubiquitinase ataxin-3, which then present increased propensity to aggregate. By analyzing MJD cell and animal models, we provide evidence that OGT is dysregulated in MJD, therefore compromising the O-GlcNAc cycle. Moreover, we demonstrate that wild-type ataxin-3 modulates OGT protein levels in a proteasomedependent manner, and we present OGT as a substrate for ataxin-3. Targeting OGT levels and activity reduced ataxin-3 aggregates, improved protein clearance and cell viability, and alleviated motor impairment reminiscent of ataxia of MJD patients in zebrafish model of the disease. Taken together, our results point to a direct interaction between OGT and ataxin-3 in health and disease and propose the O-GlcNAc cycle as a promising target for the development of therapeutics in the yet incurableMJD.

Original languageEnglish
Article numbere2025810118
Pages (from-to)1-12
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number47
Publication statusPublished - 23 Nov 2021


  • Ataxin-3
  • Machado-
  • OGlcNAc
  • OGT
  • Oseph disease
  • Spinocerebellar ataxia type 3


Dive into the research topics of 'Pathophysiological interplay between O-GlcNAc transferase and the Machado-Joseph disease protein ataxin-3'. Together they form a unique fingerprint.

Cite this