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Investigating the Conformational Stability of Prion Strains through a Kinetic Replication Model
- Source :
- PLoS Computational Biology, Vol 5, Iss 7, p e1000420 (2009), PLoS Computational Biology
- Publication Year :
- 2009
- Publisher :
- Public Library of Science (PLoS), 2009.
-
Abstract
- Prion proteins are known to misfold into a range of different aggregated forms, showing different phenotypic and pathological states. Understanding strain specificities is an important problem in the field of prion disease. Little is known about which PrPSc structural properties and molecular mechanisms determine prion replication, disease progression and strain phenotype. The aim of this work is to investigate, through a mathematical model, how the structural stability of different aggregated forms can influence the kinetics of prion replication. The model-based results suggest that prion strains with different conformational stability undergoing in vivo replication are characterizable in primis by means of different rates of breakage. A further role seems to be played by the aggregation rate (i.e. the rate at which a prion fibril grows). The kinetic variability introduced in the model by these two parameters allows us to reproduce the different characteristic features of the various strains (e.g., fibrils' mean length) and is coherent with all experimental observations concerning strain-specific behavior.<br />Author Summary Prion diseases are caused by the accumulation of a cellular prion protein with an altered conformation, which acts as a catalyst for the further recruitment and the modification of the normal form of the protein. Protein polymerization appears to have a central role in the progression of the disease, an aspect shared with several other neurodegenerative diseases. The aim of this work is to investigate at the kinetic level the “prion strain phenomenon”, i.e., the ability of prion proteins to misfold into a range of different aggregated forms exhibiting different replication and propagation properties. The dynamics of prion replication is investigated with the help of a mathematical model. We relate a measurement accessible in vitro (prion structural stability) to a mathematical description of the fibrils' kinetics in vivo. The analysis of the model suggests that the replication kinetics of the different prion strains is characterizable by means of two parameters, representing the rates of breakage and aggregation. This result is coherent with various experimental findings concerning strain-specific behavior, such as, for example, the observation of the fibril mean length of the various strains.
- Subjects :
- PrPSc Proteins
Systems biology
Prion kinetics
Epidemic models
Protein Conformation
QH301-705.5
animal diseases
Biology
Fibril
Cellular and Molecular Neuroscience
Protein structure
Infectious Diseases/Prion Diseases
Replication (statistics)
Genetics
Biology (General)
Molecular Biology
Ecology, Evolution, Behavior and Systematics
Computational Biology/Systems Biology
Ecology
Strain (chemistry)
Protein Stability
Aggregation rate
Phenotype
nervous system diseases
Kinetics
Models, Chemical
Nonlinear Dynamics
Computational Theory and Mathematics
Biochemistry
Modeling and Simulation
Linear Models
Biophysics
Conformational stability
Protein Multimerization
Research Article
Subjects
Details
- ISSN :
- 15537358
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- PLoS Computational Biology
- Accession number :
- edsair.doi.dedup.....43175163ae16f4d73dc4dddeaf7215a2