Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization.
The microtubule-associated protein tau, in a hyperphosphorylated form, aggregates into insoluble paired-helical filaments (PHFs) in Alzheimer's disease (AD) and other tauopathies. In AD, there is approximately 8 mol of phosphate per mole of tau distributed among approximately 30 PHF phosphorylation sites as compared to 2-3 mol of phosphate per mole in normal brain. In AD, kinases such as glycogen synthase kinase-3beta (GSK-3beta) are believed to be involved in the generation of hyperphosphorylated tau. However, the functional consequences of hyperphosphorylation on the microtubule binding and polymerization of tau are not well understood. To address this question, we have generated pseudohyperphosphorylation mutants consisting of six and seven sites in the proline-rich region and carboxy terminus of tau by amino acid substitution. In addition, several single, double, and triple pseudophosphorylation mutants were also generated. Pseudophosphorylation of tau decreases its affinity for microtubules, and pseudohyperphosphorylated forms of tau do not have significantly decreased levels of microtubule binding as compared to single and double sites. Three pseudohyperphosphorylated forms of tau with altered sodium dodecyl sulfate-polyacrylamide gel electrophoresis migration have a greater effect on its inducer-mediated polymerization, slowing the rate of nucleation and elongation. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.
Sun
Qian
Q
Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045, USA.
Gamblin
T Chris
TC
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D006801:Humans; D046529:Microscopy, Electron, Transmission; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011108:Polymers / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity / Q000648:ultrastructure
D011108:Polymers; D016875:tau Proteins