Research Article: A mathematical model of multisite phosphorylation of tau protein

Date Published: February 6, 2018

Publisher: Public Library of Science

Author(s): Alexander Stepanov, Tatiana Karelina, Nikolai Markevich, Oleg Demin, Timothy Nicholas, Hemant K. Paudel.

http://doi.org/10.1371/journal.pone.0192519

Abstract

Abnormal tau metabolism followed by formation of tau deposits causes a number of neurodegenerative diseases called tauopathies including Alzheimer’s disease. Hyperphosphorylation of tau protein precedes tau aggregation and is a topic of interest for the development of pharmacological interventions to prevent pathology progression at early stages. The development of a mathematical model of multisite phosphorylation of tau would be helpful for searching for the targets of pharmacological interventions and candidates for biomarkers of pathology progression. In the present study, we for the first time developed a model of multisite phosphorylation of tau protein and elucidated the relative contribution of kinases to phosphorylation of distinct sites. The model describes phosphorylation of tau or PKA-prephosphorylated tau by GSK3β and CDK5 and dephosphorylation by PP2A, accurately reproducing the data for short-term kinetics of tau (de)phosphorylation. Our results suggest that kinase inhibition may more specifically prevent tau hyperphosphorylation, e.g., on PHF sites, which are key biomarkers of pathological changes in Alzheimer’s disease. The main features of our model are partial phosphorylation of tau residues and merging of random and sequential mechanisms of multisite phosphorylation within the framework of the probability-based approach assuming independent phosphorylation events.

Partial Text

Microtubule-associated protein tau (MAPT) stabilizes microtubules regulating cell architecture and cargo transport [1]. As an intrinsically disordered protein in its unbound state, tau adopts an ensemble of conformations more or less susceptible to different modifications. The most important events leading to pathological tau aggregation are the hyperphosphorylation, conformational changes, and truncation of native tau protein [2]. The sequence and hierarchy of the events are complex and cannot be traced in vitro and especially in vivo. At the same time, various events may facilitate pathological processes or protect from them. Hyperphosphorylation of tau may be regarded as an imbalance between kinases and phosphatases owing to either activation of tau kinases or inhibition of tau phosphatases. Multisite phosphorylation is an important mechanism for regulation of a protein’s function and life-time and triggers conformational changes that alter its interactions with other proteins. More than 80 residues of tau can be potentially phosphorylated by a number of kinases [3]. Hyperphosphorylation of tau is associated with tau aggregation into fibrils and neurofibrillary tangles correlating with the development of neurodegenerative diseases: various tauopathies including Alzheimer’s disease (AD). Indeed, in vitro experiments show that phosphorylation of tau protein accelerates its aggregation into fibrils [4] of which neurofibrillary tangles consist.

A short description of the probability-based approach for description of multisite protein phosphorylation is presented below. For a detailed description, see S1 Appendix.

Tau protein is an intrinsically disordered protein and has a repertoire of conformations in equilibrium. Without any modification of each residue, there is a ratio of an open state to the sum of open and closed states. Typically, this ratio is a time-dependent function and may increase or decrease during phosphorylation, thereby reflecting the variable repertoire of conformations. The ratio should approach 1.0 when phosphorylation reaches saturation (complete phosphorylation of distinct sites), which is the shared feature of published models [19], hampering application of these approaches to short-term tau protein phosphorylation. The challenging distinct feature of our approach is the partial phosphorylation of a site for describing the short-term experiments.

In the present study, a mathematical mechanism-based model of multisite (de)phosphorylation of tau protein was developed. The main features of the model are partial phosphorylation of tau residues, and merging random and sequential mechanisms of multisite phosphorylation within the framework of the probability-based approach assuming independent phosphorylation events. This approach illustrates how analysis of in vitro kinetics allows for the choice of better candidates and for a greater understanding of relations between therapeutic targets and biomarkers. The model describes phosphorylation of tau or PKA-prephosphorylated tau by GSK3β and CDK5 and dephosphorylation by PP2A, thereby accurately reproducing the data on short-term kinetics of tau (de)phosphorylation. Our results suggest that kinase inhibition may prevent tau hyperphosphorylation more specifically, e.g., on PHF sites, which are the key biomarkers of AD pathology. The model may serve as a submodel for subsequent development of a systems pharmacological model of tau pathology for research into biologically relevant challenges.

 

Source:

http://doi.org/10.1371/journal.pone.0192519

 

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