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 2 Correspondence: 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@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
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Regulation between O-GlcNAcylation and phosphorylation of neurofilament-M and their dysregulation in Alzheimer disease
Deng, Yanqiu; Li, Bin; Liu, Fei; Iqbal, Khalid; Grundke-Iqbal, Inge; Brandt, Roland; Gong, Cheng-Xin
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, Volume 22 (1): 138
Fed of American Socs for Experimental Biology – Jan 1, 2008
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