Vulnerabilities in the Tau Network and the Role of Ultrasensitive Points in Tau Pathophysiology

Theresa M Yuraszeck,Anne Robinson,Maria Rodriguez-Fernandez,Pierre Neveu,Francis J Doyle,Kenneth S Kosik,Weixiong Zhang

doi:10.1371/journal.pcbi.1000997

Theresa M Yuraszeck, Anne Robinson + Show 5 more

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https://doi.org/10.1371/journal.pcbi.1000997

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Abstract

The multifactorial nature of disease motivates the use of systems-level analyses to understand their pathology. We used a systems biology approach to study tau aggregation, one of the hallmark features of Alzheimer's disease. A mathematical model was constructed to capture the current state of knowledge concerning tau's behavior and interactions in cells. The model was implemented in silico in the form of ordinary differential equations. The identifiability of the model was assessed and parameters were estimated to generate two cellular states: a population of solutions that corresponds to normal tau homeostasis and a population of solutions that displays aggregation-prone behavior. The model of normal tau homeostasis was robust to perturbations, and disturbances in multiple processes were required to achieve an aggregation-prone state. The aggregation-prone state was ultrasensitive to perturbations in diverse subsets of networks. Tau aggregation requires that multiple cellular parameters are set coordinately to a set of values that drive pathological assembly of tau. This model provides a foundation on which to build and increase our understanding of the series of events that lead to tau aggregation and may ultimately be used to identify critical intervention points that can direct the cell away from tau aggregation to aid in the treatment of tau-mediated (or related) aggregation diseases including Alzheimer's.

Highlights

Despite the fidelity of protein folding and the operation of quality control mechanisms to eliminate misfolded and otherwise abnormal proteins, a number of diseases can be traced to defects in these processes [1]
The deficits in spatial learning and memory observed in mouse models expressing human APP can be ameliorated by reducing endogenous, wild-type tau [11], which protects against early mortality and inhibits excitoxicity; this finding is supported by more recent experiments in an AB-forming mouse model [12]
Alternative splicing of other tau exons was not considered in the model; we modeled two species to be representative of the 3R and 4R classes

Summary

Introduction

Despite the fidelity of protein folding and the operation of quality control mechanisms to eliminate misfolded and otherwise abnormal proteins, a number of diseases can be traced to defects in these processes [1]. The deficits in spatial learning and memory observed in mouse models expressing human APP can be ameliorated by reducing endogenous, wild-type tau [11], which protects against early mortality and inhibits excitoxicity; this finding is supported by more recent experiments in an AB-forming mouse model [12]. Taken together, these studies point to tau as a key causative factor in neurodegeneration and suggest that the tau pathway itself represents a reasonable therapeutic target for diseases in which the abnormal tau processing pathway is triggered

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