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

Budrikis Z, Costantini G, La Porta CA, Zapperi S - Nat Commun (2014)

Bottom Line: 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.The model can be successfully used to interpret experimental data on amyloid-β clearance from the central nervous system.

View Article: PubMed Central - PubMed

Affiliation: Institute for Scientific Interchange Foundation, Via Alassio 11/C, Torino 10126, Italy.

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.

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Related in: MedlinePlus

Effective polymerization rate from numerical simulations.The effective polymerization rate is computed from 3D simulations for different values of kout and H. The peak corresponds to the phase transition. The same data plotted as a function of  show a collapse only below the phase transition (inset).
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f8: Effective polymerization rate from numerical simulations.The effective polymerization rate is computed from 3D simulations for different values of kout and H. The peak corresponds to the phase transition. The same data plotted as a function of show a collapse only below the phase transition (inset).

Mentions: Three dimensional simulations of protein aggregation display qualitative agreement with mean-field theory in conditions that should apply to experiments in vitro and in vivo. Quantitative differences between the two models are mainly owing to the absence of geometrical features in the mean-field model. Investigating the role of spatial confinement is important because large local fluctuations can drive polymerization in small systems. To this end, we use 3D simulations to estimate the size-dependence of some effective mean-field parameters such as the polymerization and degradation rates, as a function of kout and H. The effective degradation rate depends on the sample size H in three dimensions because proteins can exit only through the boundaries, a feature that is absent in the mean-field model (see Fig. 7). The effective polymerization rate displays a peak as a function of kout, in correspondence with the phase transition (Fig. 8). Furthermore, for smaller system sizes the polymerization rate is larger.


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

Budrikis Z, Costantini G, La Porta CA, Zapperi S - Nat Commun (2014)

Effective polymerization rate from numerical simulations.The effective polymerization rate is computed from 3D simulations for different values of kout and H. The peak corresponds to the phase transition. The same data plotted as a function of  show a collapse only below the phase transition (inset).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4048836&req=5

f8: Effective polymerization rate from numerical simulations.The effective polymerization rate is computed from 3D simulations for different values of kout and H. The peak corresponds to the phase transition. The same data plotted as a function of show a collapse only below the phase transition (inset).
Mentions: Three dimensional simulations of protein aggregation display qualitative agreement with mean-field theory in conditions that should apply to experiments in vitro and in vivo. Quantitative differences between the two models are mainly owing to the absence of geometrical features in the mean-field model. Investigating the role of spatial confinement is important because large local fluctuations can drive polymerization in small systems. To this end, we use 3D simulations to estimate the size-dependence of some effective mean-field parameters such as the polymerization and degradation rates, as a function of kout and H. The effective degradation rate depends on the sample size H in three dimensions because proteins can exit only through the boundaries, a feature that is absent in the mean-field model (see Fig. 7). The effective polymerization rate displays a peak as a function of kout, in correspondence with the phase transition (Fig. 8). Furthermore, for smaller system sizes the polymerization rate is larger.

Bottom Line: 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.The model can be successfully used to interpret experimental data on amyloid-β clearance from the central nervous system.

View Article: PubMed Central - PubMed

Affiliation: Institute for Scientific Interchange Foundation, Via Alassio 11/C, Torino 10126, Italy.

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.

Show MeSH
Related in: MedlinePlus