Title

Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer's disease.

Journal

Biochimica et biophysica acta

Volume

1800

Issue

None

Pages

67-79

Date

2010-02-01

Authors

Dehennaut V | Drougat L | Guinez C | Lefebvre T | Michalski JC | Mir AM | Mortuaire M | Olivier S | Vercoutter-Edouart AS

This post-translational modification is likely an indicator of good health since its intracellular level correlates with the availability of extracellular glucose. From a more practical point of view, it has been shown that O-GlcNAcylation impairments contribute to the etiology of cardiovascular diseases, type-2 diabetes and Alzheimer's disease (AD), three illnesses common in occidental societies.

It has been reported that the proteasomal machinery is modified by O-GlcNAcylation [53,126] and that after modification by OGT, the proteasome is inhibited [53]. Intriguingly, it has been proposed that a genetic impairment in the OGA gene results in proteasomal dysfunction through a lack of hydrolysis of the inhibitory O-GlcNAc residues of the 19S regulatory cap. Indeed, the OGA gene is located in the 10q locus [127,128], a chromosomal region frequently mutated in AD. The impairment of OGA in AD and the subsequent static OGlcNAcylation of the proteasome may explain why the latter fails to degrade neuronal aggregates. In addition, it has been reported that OGlcNAcylation reduces the sensitivity of intracellular proteins to proteasomal degradation by directly modifying them [43,129,130]. The two phenomena could thus act synergistically: a protein could escape degradation by means of its own O-GlcNAcylation and by the inhibitory effect of glycosylation on the proteasome, leading to a considerable decrease in the turnover of proteins that in turn may aggregate and cause neuronal death.

These results are in accord with our previous study showing that Tau hyperphosphorylation is associated with a decrease in its O-GlcNAcylation level. A recent observation argues for the hypothesis that O-GlcNAcylation occurs first and that its modification reflects on the phosphorylation status.

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