Pathophysiological interplay between O-GlcNAc transferase and the Machado-Joseph disease protein ataxin-3
Summary
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 proteasome-dependent 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 incurable MJD.
| Authors | Pereira Sena P, Weber JJ, Watchon M, Robinson KJ, Wassouf Z, Hauser S, Helm J, Abeditashi M, Schmidt J, Hübener-Schmid J, Schöls L, Laird AS, Riess O, Schmidt T |
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| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Publication Date | 2021 Nov 23;118(47) |
| PubMed | 34785590 |
| PubMed Central | PMC8617493 |
| DOI | 10.1073/pnas.2025810118 |