There is still no clear understanding what is the driving force of AD progression. The main hypotheses of the pathology are based on amyloid beta plaques or tau protein aggregation.
‘Quantitative systems pharmacology (QSP) modeling approach may illustrate how analysis of in vitro kinetics may help choose better candidates for a greater understanding of relations between therapeutic targets and biomarkers.’
Tau protein (or MAPT, microtubule-associated protein tau) stabilizes the cytoskeleton in normal cells, but it doesn't function properly in neurons of AD patients, it undergoes hyperphosphorylation and aggregates into neurofibrillary tangles within neurons.
Normally, only some of the numerous phosphorylation sites of tau are phosphorylated. Therefore drugs for the tauopathies treatment could target pathological tau phosphorylation.
Different phosphorylation states contribute unequally in the pathology. So understanding the relative contribution of each kinase and phosphatase to phosphorylation of distinct sites is important for searching the principal drug targets. This was the goal of the work.
If a protein has n phosphorylation sites, then there are 2n possible phosphorylation states. Furthermore, the sequence of protein phosphorylation and dephosphorylation processes is regulated in a complicated way. The model developers assumed that phosphorylation of distinct sites is partially independent. It allowed to overcome the combinatorial explosion problem.
Four kinases (GSK3β, PKA, CDK5, and p38γ) and one phosphatase (PP2A) were selected from the plurality of tau (de)phosphorylating enzymes. Ten phosphorylation sites which are of specific interest for the clinical research were selected from a few dozens of potentially phosphorylable sites of tau protein.
This selection was based on the published experimental data. The modelers also have incorporated so-called pseudo residue which described phosphorylation sites aside from the ten described above. This is the first effort of estimation of tau protein state sensitivity to key enzymes using real kinetic data.
"We've taken the first step in the understanding of (de)phosphorylation patterns of each tau protein residue by different enzymes. Our model may suggest the role of each tau kinase or phosphatase plays in AD pathogenesis as well as the most potent targets for its treatment," commented Alexander Stepanov, the leading contributor to the article.