Pathophysiological interplay between <i>O</i>-GlcNAc transferase and the Machado-Joseph disease protein ataxin-3.

Abstract

Aberrant <i>O</i>-GlcNAcylation, a protein posttranslational modification defined by the <i>O</i>-linked attachment of the monosaccharide <i>N</i>-acetylglucosamine (<i>O</i>-GlcNAc), has been implicated in neurodegenerative diseases. However, although many neuronal proteins are substrates for <i>O</i>-GlcNAcylation, this process has not been extensively investigated in polyglutamine disorders. We aimed to evaluate the enzyme <i>O</i>-GlcNAc transferase (OGT), which attaches <i>O</i>-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 <i>O</i>-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 <i>O</i>-GlcNAc cycle as a promising target for the development of therapeutics in the yet incurable MJD.