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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

Polymer sizes display critical fluctuations close to the phase transition.(a) The average polymer length in a single simulation displays fluctuations with intermittent bursts that are reminiscent of crackling noise. (b) The distribution of burst durations follows a power law distribution up to a characteristic cutoff that increases as the transition is approached. Above the transition, we observe large events that should be limited by system size. (c) Different distributions can be collapsed onto a universal scaling function.
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f6: Polymer sizes display critical fluctuations close to the phase transition.(a) The average polymer length in a single simulation displays fluctuations with intermittent bursts that are reminiscent of crackling noise. (b) The distribution of burst durations follows a power law distribution up to a characteristic cutoff that increases as the transition is approached. Above the transition, we observe large events that should be limited by system size. (c) Different distributions can be collapsed onto a universal scaling function.

Mentions: To confirm that we are in presence of a critical phase transition, we study the temporal fluctuations of the average polymer length in 3D simulations. As shown in Fig. 6a for a single realization of the process, the polymer length undergoes an intermittent dynamics with bursty activity that is reminiscent of the crackling noise observed in materials close to non-equilibrium phase transitions35. We characterize the statistical properties of the signal by measuring the distribution of pulse durations T and sizes s, defined as the area under a pulse, for different values of kout. Figure 6b shows that for , bursts display a power law distribution with a cutoff that diverges at the transition. In the growing phase, the distribution develops a peak at large T typical of system-wide spanning events. We fit all the subcritical distributions simultaneously by the scaling function


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

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

Polymer sizes display critical fluctuations close to the phase transition.(a) The average polymer length in a single simulation displays fluctuations with intermittent bursts that are reminiscent of crackling noise. (b) The distribution of burst durations follows a power law distribution up to a characteristic cutoff that increases as the transition is approached. Above the transition, we observe large events that should be limited by system size. (c) Different distributions can be collapsed onto a universal scaling function.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Polymer sizes display critical fluctuations close to the phase transition.(a) The average polymer length in a single simulation displays fluctuations with intermittent bursts that are reminiscent of crackling noise. (b) The distribution of burst durations follows a power law distribution up to a characteristic cutoff that increases as the transition is approached. Above the transition, we observe large events that should be limited by system size. (c) Different distributions can be collapsed onto a universal scaling function.
Mentions: To confirm that we are in presence of a critical phase transition, we study the temporal fluctuations of the average polymer length in 3D simulations. As shown in Fig. 6a for a single realization of the process, the polymer length undergoes an intermittent dynamics with bursty activity that is reminiscent of the crackling noise observed in materials close to non-equilibrium phase transitions35. We characterize the statistical properties of the signal by measuring the distribution of pulse durations T and sizes s, defined as the area under a pulse, for different values of kout. Figure 6b shows that for , bursts display a power law distribution with a cutoff that diverges at the transition. In the growing phase, the distribution develops a peak at large T typical of system-wide spanning events. We fit all the subcritical distributions simultaneously by the scaling function

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