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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

Model of protein aggregation in the endoplasmic reticulum.(a) The ER is a set of channel-like structures surrounding the nucleus of the cell. (b) We focus on a portion of the ER bounded by two square surfaces placed at distance H. Protein monomers are assigned to the nodes of a 3D square lattice. We report a typical configuration obtained from the simulations where polymers are coloured differently according to their length. (c) Inside the ER, proteins can diffuse, aggregate and fragment. They can also enter and exit from the ER channel with given rates. (d) We also consider the possibility that proteins can aggregate only after becoming active and to transform into a latent state where aggregation is prevented.
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f1: Model of protein aggregation in the endoplasmic reticulum.(a) The ER is a set of channel-like structures surrounding the nucleus of the cell. (b) We focus on a portion of the ER bounded by two square surfaces placed at distance H. Protein monomers are assigned to the nodes of a 3D square lattice. We report a typical configuration obtained from the simulations where polymers are coloured differently according to their length. (c) Inside the ER, proteins can diffuse, aggregate and fragment. They can also enter and exit from the ER channel with given rates. (d) We also consider the possibility that proteins can aggregate only after becoming active and to transform into a latent state where aggregation is prevented.

Mentions: We consider a 3D model of linear polymer aggregation in a confined space simulating an intracellular organelle like the ER, a set of channel-like structures surrounding the cell nucleus (see Fig. 1 for an illustration of the model and the Methods section for a detailed description). To validate our model in a well-studied scenario, we first consider the kinetics of a typical in vitro experiment and perform 3D numerical simulations of linear polymer diffusion and aggregation at constant concentration and temperature (with kout=kin=0 and periodic boundary conditions as discussed above). While the model is general for linear polymers, we focus here on neuroserpin, which has been shown to undergo processes of activation and latentization3334.


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

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

Model of protein aggregation in the endoplasmic reticulum.(a) The ER is a set of channel-like structures surrounding the nucleus of the cell. (b) We focus on a portion of the ER bounded by two square surfaces placed at distance H. Protein monomers are assigned to the nodes of a 3D square lattice. We report a typical configuration obtained from the simulations where polymers are coloured differently according to their length. (c) Inside the ER, proteins can diffuse, aggregate and fragment. They can also enter and exit from the ER channel with given rates. (d) We also consider the possibility that proteins can aggregate only after becoming active and to transform into a latent state where aggregation is prevented.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Model of protein aggregation in the endoplasmic reticulum.(a) The ER is a set of channel-like structures surrounding the nucleus of the cell. (b) We focus on a portion of the ER bounded by two square surfaces placed at distance H. Protein monomers are assigned to the nodes of a 3D square lattice. We report a typical configuration obtained from the simulations where polymers are coloured differently according to their length. (c) Inside the ER, proteins can diffuse, aggregate and fragment. They can also enter and exit from the ER channel with given rates. (d) We also consider the possibility that proteins can aggregate only after becoming active and to transform into a latent state where aggregation is prevented.
Mentions: We consider a 3D model of linear polymer aggregation in a confined space simulating an intracellular organelle like the ER, a set of channel-like structures surrounding the cell nucleus (see Fig. 1 for an illustration of the model and the Methods section for a detailed description). To validate our model in a well-studied scenario, we first consider the kinetics of a typical in vitro experiment and perform 3D numerical simulations of linear polymer diffusion and aggregation at constant concentration and temperature (with kout=kin=0 and periodic boundary conditions as discussed above). While the model is general for linear polymers, we focus here on neuroserpin, which has been shown to undergo processes of activation and latentization3334.

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