The effect of time-dependent macromolecular crowding on the kinetics of protein aggregation: a simple model for the onset of age-related neurodegenerative disease

Allen P Minton

doi:10.3389/fphy.2014.00048

Abstract

A linear increase in the concentration of "inert" macromolecules with time is incorporated into simple excluded volume models for protein condensation or fibrillation. Such models predict a long latent period during which no significant amount of protein aggregates, followed by a steep increase in the total amount of aggregate. The elapsed time at which these models predict half-conversion of model protein to aggregate varies by less than a factor of two when the intrinsic rate constant for condensation or fibril growth of the protein is varied over many orders of magnitude. It is suggested that this concept can explain why the symptoms of neurodegenerative diseases associated with the aggregation of very different proteins and peptides appear at approximately the same advanced age in humans.

Highlights

Several neurodegenerative diseases, most prominent among them Alzheimer’s Dementia and Parkinsonism, are extremely rare in individuals under the age of about sixty, but the incidence rises sharply above that age, reaching 10–25% at the age of eighty [1, 2]
The root cause of age-related incidence has been the subject of much conjecture (Google “aging and neurodegeneration”) but no solid consensus has been formed. The purpose of this communication is to suggest a common mechanism underlying the age-related onset of a variety of neurodegenerative diseases based upon the effect of excluded volume on the kinetics of protein aggregation
A simple model based upon excluded volume theory was shown to quantitatively account for the dependence of the kinetics of amyloid fiber formation upon the concentration of added polymer [10]

Summary

Introduction

Most prominent among them Alzheimer’s Dementia and Parkinsonism, are extremely rare in individuals under the age of about sixty, but the incidence rises sharply above that age, reaching 10–25% at the age of eighty [1, 2]. A linear increase in the concentration of “inert” macromolecules with time is incorporated into simple excluded volume models for protein condensation or fibrillation.

Results

Conclusion