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Regulation between O-GlcNAcylation and phosphorylation of neurofilament-M and their dysregulation in Alzheimer disease

Yanqiu Deng^*,1, Bin Li^*, Fei Liu^*, Khalid Iqbal^*, Inge Grundke-Iqbal^*, Roland Brandt and Cheng-Xin Gong^*,2

^* Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA; and

Department of Neurobiology, University of Osnabruck, Osnabruck, Germany

²Correspondence: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Rd., Staten Island, NY 10314, USA. E-mail: cxgong{at}mail.csi.cuny.edu

The medium subunit of neurofilament (NF-M) is extensively modified by phosphate and O-linked β-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.

Key Words: glycosylation • cytoskeleton • glucose metabolism

This article has been cited by other articles:

				F. Liu, J. Shi, H. Tanimukai, J. Gu, J. Gu, I. Grundke-Iqbal, K. Iqbal, and C.-X. Gong Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease Brain, July 1, 2009; 132(7): 1820 - 1832. [Abstract] [Full Text] [PDF]