Protein accumulation in the endoplasmic reticulum as a non-equilibrium phase transition.

Zoe Budrikis,Caterina A M La Porta,Stefano Zapperi,Giulio Costantini

doi:10.1038/ncomms4620

Abstract

Several neurological disorders are associated with the aggregation of aberrant proteins, often localized in intracellular organelles such as the endoplasmic reticulum. Here we study protein aggregation kinetics by mean-field reactions and three dimensional Monte carlo simulations of diffusion-limited aggregation of linear polymers in a confined space, representing the endoplasmic reticulum. By tuning the rates of protein production and degradation, we show that the system undergoes a non-equilibrium phase transition from a physiological phase with little or no polymer accumulation to a pathological phase characterized by persistent polymerization. A combination of external factors accumulating during the lifetime of a patient can thus slightly modify the phase transition control parameters, tipping the balance from a long symptomless lag phase to an accelerated pathological development. The model can be successfully used to interpret experimental data on amyloid-β clearance from the central nervous system.

Highlights

Several neurological disorders are associated with the aggregation of aberrant proteins, often localized in intracellular organelles such as the endoplasmic reticulum
Serpinopathies result from point mutations in a1-antitrypsin and neuroserpin showing a delay in folding, with unstable intermediates being cleared by endoplasmic reticulum (ER)associated degradation (ERAD)[1,2,3]
The traditional theoretical framework to understand protein polymerization involved in these neurological disorders is based on either molecular dynamics simulations, which give an understanding of how individual proteins interact[23,24], or on kinetic rate equations, which yield the growth of the polymers in a mean-field approximation[25,26,27,28,29,30,31]

Summary

Introduction

Several neurological disorders are associated with the aggregation of aberrant proteins, often localized in intracellular organelles such as the endoplasmic reticulum. By tuning the rates of protein production and degradation, we show that the system undergoes a non-equilibrium phase transition from a physiological phase with little or no polymer accumulation to a pathological phase characterized by persistent polymerization. A number of neurological pathologies, including Alzheimer’s disease (AD) and Parkinson’s disease, spongiform encephalopathies and serpinopathies, are collectively identified as conformational diseases because they are all characterized by the aggregation and tissue deposition of aberrant conformations of proteins. Recent results show an overproduction of aggregation-prone amyloid b42, which might interest the ER13 This is confirmed by the analysis of the brains of AD patients displaying ER dysfunction[14,15], in the ERAD pathways[16]. The conditions are, not physiological because in the cell proteins undergo a well regulated cycle of synthesis by the ribosome and subsequent degradation through secretory pathways

Methods

Results

Conclusion