Journal
FASEB JOURNAL
Volume 22, Issue 1, Pages 138-145Publisher
WILEY
DOI: 10.1096/fj.07-8309com
Keywords
glycosylation; cytoskeleton; glucose metabolism
Categories
Funding
- NATIONAL INSTITUTE ON AGING [P30AG019610, R01AG019158, R01AG027429] Funding Source: NIH RePORTER
- NIA NIH HHS [R01 AG027429-02, AG027429, P30 AG19610, P30 AG019610, AG019158, R01 AG019158, R01 AG027429-01, R01 AG027429] Funding Source: Medline
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The medium subunit of neurofilament (NF-M) is extensively modified by phosphate and O-linked beta-N-acetylglucosamine (O-GlcNAc). Phosphorylation of NF-M plays a critical role in regulating its translocation, filament formation, and function. However, the regulation of NF-M phosphorylation and the role of NF-M O-GlcNAcylation (a modification by which GlcNAc is attached to the serine/threonine residues of a protein via an O-linked glycosidic bond) are largely unknown. Here, we demonstrate that O-GlcNAcylation and phosphorylation of NF-M regulate each other reciprocally in cultured neuroblastoma cells and in metabolically active rat brain slices. In animal models of fasting rats, which mimicked the decreased glucose uptake/metabolism observed in brains of individuals with Alzheimer disease (AD), we found a decrease in O-GlcNAcylation and increase in phosphorylation of NF-M. We also observed decreased O-GlcNAcylation and an increased phosphorylation of NF-M in AD brain. These results suggest that O-GlcNAcylation and phosphorylation of NF-M are regulated reciprocally and that the hyperphosphorylation and accumulation of NF-M in AD brain might be caused by impaired brain glucose uptake/metabolism via down-regulation of NF-M O-GlcNAcylation. -Deng, Y., Li, B., Liu, F., Iqbal, K., Grundke-Iqbal, I., Brandt, R., Gong, C.-X. Regulation between O-GlcNAcylation and phosphorylation of neurofilament-M and their dysregulation in Alzheimer disease.
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