B vitamin deficiency promotes tau phosphorylation through regulation of GSK3beta and PP2A.
Neurofibrillary tangles (NFTs), composed of intracellular filamentous aggregates of hyperphosphorylated protein tau, are one of the pathological hallmarks of Alzheimer's disease (AD). Tau phosphorylation is regulated by the equilibrium between activities of its protein kinases and phosphatases; unbalance of these activities is proposed to be a reasonable causative factor to the disease process. Glycogen synthase kinase 3beta (GSK3beta) is one of the most important protein kinase in regulating tau phosphorylation; overexpression of active GSK3beta causes ADlike hyperphosphorylation of tau. Protein phosphatase 2A (PP2A) is the major phosphatase that dephosphorylates tau; it was demonstrated that highly conserved carboxyl-terminal sequence of PP2A C-subunit is a focal point for phosphatase regulation. This is the site of a reversible methyl esterification reaction that controls AB<formula>_{alpha}</formula>C heterotrimers formation. Here we demonstrate that GSK3beta and PP2A genes were upregulated by inhibiting methylation reactions through B vitamin deficiency. In this condition, methylated catalytic subunit PP2Ac was decreased, leading to reduced PP2A activity. By contrast, we observed GSK3beta protein increase and a modulation in phosphorylation sites that regulate GSK3beta activity. Therefore, one-carbon metabolism alteration seems to be a cause of deregulation of the equilibrium between GSK3beta and PP2A, leading to abnormal hyperphosphorylated tau.
Department of Surgery P. Valdoni, Sapienza University of Rome, Rome, Italy.
Vincenzina
V
Nicolia
Andrea
A
Fuso
Rosaria A
RA
Cavallaro
Andrea
A
Di Luzio
Sigfrido
S
Scarpa
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009410:Nerve Degeneration / Q000209:etiology / Q000473:pathology; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014804:Vitamin B Deficiency / Q000503:physiopathology*; D016875:tau Proteins / Q000378:metabolism*
D017931:DNA Primers; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2