Regulation between O-GlcNAcylation and phosphorylation of neurofilament-M and their dysregulation in Alzheimer disease.
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.
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Rd., Staten Island, NY 10314, USA.
Yanqiu
Y
Deng
Bin
B
Li
Fei
F
Liu
Khalid
K
Iqbal
Inge
I
Grundke-Iqbal
Roland
R
Brandt
Cheng-Xin
CX
Gong
D000215:Acylation; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005944:Glucosamine / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D016900:Neurofilament Proteins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats
D016900:Neurofilament Proteins; C061195:neurofilament protein M; D005947:Glucose; D005944:Glucosamine