Does O-GlcNAc play a role in neurodegenerative diseases?
There are several lines of evidence that the modification of proteins by cytosolic- and nuclear-specific O-linked N-acetylglucosamine (O-GlcNAc) glycosylation is closely related to neuropathologies, particularly Alzheimer's disease. Several neuronal proteins have been identified as being modified with O-GlcNAc; these proteins could form part of the inclusion bodies found, for example, in the most frequently observed neurologic disorder (i.e., Alzheimer's disease; Tau protein and beta-amyloid peptide are the well known aggregated proteins). O-GlcNAc proteins are also implicated in synaptosomal transport (e.g., synapsins and clathrin-assembly proteins). Inclusion bodies are partly characterized by a deficiency in the ubiquitin-proteasome system, avoiding the degradation of aggregated proteins. From this perspective, it appears interesting that substrate proteins could be protected against proteasomal degradation by being covalently modified with single N-acetylglucosamine on serine or threonine, and that the proteasome itself is modified and regulated by O-GlcNAc (in this case the turnover of neuronal proteins correlates with extracellular glucose). Interestingly, glucose uptake and metabolism are impaired in neuronal disorders, and this phenomenon is linked to increased phosphorylation. In view of the existence of the dynamic interplay between O-GlcNAc and phosphorylation, it is tempting to draw a parallel between the use of glucose, O-GlcNAc glycosylation and phosphorylation. Lastly, the two enzymes responsible for O-GlcNAc dynamism (i.e., O-GlcNAc transferase and glucosaminidase) are both enriched in the brain and genes that encode the two enzymes are located in two regions that are found to be frequently mutated in neurologic disorders. The data presented in this review strongly suggest that O-GlcNAc could play an active role in neurodegenerative diseases.
Lefebvre
Tony
T
UMR 8576, Centre National de la Recherche Scientifique , Laboratoire de Chimie-Biologique, Bâtiment C9, 59655 Villeneuve d'Ascq, France. tony.lefebvre@univ-lille1.fr
Guinez
Céline
C
Dehennaut
Vanessa
V
Beseme-Dekeyser
Olivia
O
Morelle
Willy
W
Michalski
Jean-Claude
JC
D000117:Acetylglucosamine / Q000502:physiology*; D000118:Acetylglucosaminidase / Q000502:physiology; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000503:physiopathology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D033921:Vesicular Transport Proteins / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D009419:Nerve Tissue Proteins; D033921:Vesicular Transport Proteins; D016875:tau Proteins; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; D000118:Acetylglucosaminidase; D046988:Proteasome Endopeptidase Complex; D005947:Glucose; D000117:Acetylglucosamine