Pathophysiological interplay between O -GlcNAc transferase and the Machado–Joseph disease protein ataxin-3
| Autor: | Mahkameh Abeditashi, Katherine J. Robinson, Jacob Helm, Thorsten Schmidt, Olaf Riess, Jonasz J. Weber, Zinah Wassouf, Stefan Hauser, Ludger Schöls, Jana Schmidt, Maxinne Watchon, Angela S. Laird, Priscila Pereira Sena, Jeannette Hübener-Schmid |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Proteasome Endopeptidase Complex
congenital hereditary and neonatal diseases and abnormalities Ataxia Cell Biology N-Acetylglucosaminyltransferases Deubiquitinating enzyme metabolism [N-Acetylglucosaminyltransferases] genetics [Ataxin-3] Spinocerebellar ataxia type 3 ataxin-3 medicine Animals Humans Transferase metabolism [Zebrafish] Viability assay Zebrafish Multidisciplinary metabolism [Ataxin-3] medicine.disease biology.organism_classification Cell biology Disease Models Animal HEK293 Cells medicine.anatomical_structure Ataxin O-GlcNAc transferase pathology [Machado-Joseph Disease] O-GlcNAc OGT biology.protein ddc:500 metabolism [Machado-Joseph Disease] medicine.symptom Peptides polyglutamine Machado–Joseph disease |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America 118(47), e2025810118 (2021). doi:10.1073/pnas.2025810118 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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