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P2‐166: Atomic structure of the PHF core C‐terminus
Author(s) -
Handzusova Martina,
Ivanovova Natalia,
Sevcik Jozef,
Skrabana Rostislav,
Iqbal Khalid,
Novak Michal
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.1240
Subject(s) - chemistry , core (optical fiber) , crystallography , c terminus , crystallization , tau protein , nuclear magnetic resonance spectroscopy , biophysics , stereochemistry , biochemistry , alzheimer's disease , pathology , materials science , biology , disease , medicine , amino acid , organic chemistry , composite material
ease (AD) there are the neurofibrillary tangles (NFTs) composed of intracellular filamentous aggregates of hyperphosphorylated protein tau. Generally, the level of tau phosphorylation is regulated by the equilibrium between the activities of its protein kinases and phosphatases. An imbalanced regulation in protein kinase and protein phosphatase is proposed to be a reasonable causative factor to the disease process. One protein kinase that play an important role in regulating the phosphorilation state of tau is glycogen synthase kinase (Gsk) 3 . Recent studies show that overexpression of active Gsk3 results in AD. The major phosphatase that dephosphorylates tau is protein phosphatase 2A (PP2A). PP2A is a trimeric serine/threonine protein phosphatase composed of three subunits. Different groups showed that the 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 the formation of AB C heterotrimers. Objective(s): The aim of this study is to demonstrate that hypomethylation regulates the equilibrium between protein kinase and phosphatase activities, leading to abnormal hyperphosphorylated tau. Methods: Both SK-N-BE neuroblastoma cell line and TgCRND8 mice were used. In vitro, we used culture media without folate, B12 and B6, whereas in vivo, mice were fed with a diet deficient of the same vitamins. We analyzed expression levels of kinase and phosphatase with quantitative Real-Time PCR, western blot and activity assay. Results: We demonstrated that Gsk3 and PP2A genes were upregulated by inhibiting methylation reactions. Western blot analysis illustrate that methylated PP2A was decreased leading to reduced PP2A activity. By contrast, the levels of Gsk3 protein increased in the same condition. Conclusions: The analysis of Tau and the toxic tau fragments demonstrate that lowered SAM levels are the cause of deregulation of the equilibrium between Gsk3 and PP2A activities.