| Autor: |
Priscila, Pereira Sena, Jonasz J, Weber, Maxinne, Watchon, Katherine J, Robinson, Zinah, Wassouf, Stefan, Hauser, Jacob, Helm, Mahkameh, Abeditashi, Jana, Schmidt, Jeannette, Hübener-Schmid, Ludger, Schöls, Angela S, Laird, Olaf, Riess, Thorsten, Schmidt |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Proc Natl Acad Sci U S A |
| ISSN: |
1091-6490 |
| 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 |
| Externí odkaz: |
|
