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Regulation between O‐GlcNAcylation and phosphorylation of neurofilament‐M and their dysregulation in Alzheimer disease
Author(s) -
Deng Yanqiu,
Li Bin,
Liu Fei,
Iqbal Khalid,
GrundkeIqbal Inge,
Brandt Roland,
Gong ChengXin
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-8309com
Subject(s) - phosphorylation , hyperphosphorylation , neurofilament , threonine , serine , microbiology and biotechnology , kinase , protein subunit , chemistry , neurodegeneration , medicine , biology , endocrinology , biochemistry , disease , immunohistochemistry , gene
The medium subunit of neurofilament (NF‐M) is extensively modified by phosphate and O‐linked β‐N‐acetylglucosamine (O‐GlcNAc). Phosphory‐lation 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 neuro‐blastoma 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. FASEB J. 22, 138–145 (2008)