Dataset Information

Masel2000 - Drugs to stop prion aggregates and other amyloids

ABSTRACT: Masel2000 - Drugs to stop prion aggregates and other amyloids Encoded non-curated model. Issues: - Missing initial concentration for species y, yb and z - Not reproducible figures This model is described in the article: Designing drugs to stop the formation of prion aggregates and other amyloids. Masel J, Jansen VA. Biophys. Chem. 2000 Dec; 88(1-3): 47-59 Abstract: Amyloid protein aggregates are implicated in many neurodegenerative diseases, including Alzheimer's disease and the prion diseases. Therapeutics to block amyloid formation are often tested in vitro, but it is not clear how to extrapolate from these experiments to a clinical setting, where the effective drug dose may be much lower. Here we address this question using a theoretical kinetic model to calculate the growth rate of protein aggregates as a function of the dose of each of three categories of drug. We find that therapeutics which block the growing ends of amyloids are the most promising, as alternative strategies may be ineffective or even accelerate amyloid formation at low drug concentrations. Our mathematical model can be used to identify and optimise an end-blocking drug in vitro. Our model also suggests an alternative explanation for data previously thought to prove the existence of an entity known as protein X. This model is hosted on BioModels Database and identified by: MODEL1410310000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

DISEASE(S): Huntington's Disease,Alzheimer's Disease,Parkinson's Disease

SUBMITTER: Audald Lloret i Villas

PROVIDER: MODEL1410310000 | BioModels | 2015-04-15

REPOSITORIES: BioModels

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Publications

Designing drugs to stop the formation of prion aggregates and other amyloids.

Masel J J Jansen V A VA

Biophysical chemistry 20001201 1-3

Amyloid protein aggregates are implicated in many neurodegenerative diseases, including Alzheimer's disease and the prion diseases. Therapeutics to block amyloid formation are often tested in vitro, but it is not clear how to extrapolate from these experiments to a clinical setting, where the effective drug dose may be much lower. Here we address this question using a theoretical kinetic model to calculate the growth rate of protein aggregates as a function of the dose of each of three categorie ...[more]

PMID: 11152275

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Project description:Crespo2012 - Kinetics of Amyloid Fibril Formation This model is described in the article: A generic crystallization-like model that describes the kinetics of amyloid fibril formation. Crespo R, Rocha FA, Damas AM, Martins PM. J. Biol. Chem. 2012 Aug; 287(36): 30585-30594 Abstract: Associated with neurodegenerative disorders such as Alzheimer, Parkinson, or prion diseases, the conversion of soluble proteins into amyloid fibrils remains poorly understood. Extensive "in vitro" measurements of protein aggregation kinetics have been reported, but no consensus mechanism has emerged until now. This contribution aims at overcoming this gap by proposing a theoretically consistent crystallization-like model (CLM) that is able to describe the classic types of amyloid fibrillization kinetics identified in our literature survey. Amyloid conversion represented as a function of time is shown to follow different curve shapes, ranging from sigmoidal to hyperbolic, according to the relative importance of the nucleation and growth steps. Using the CLM, apparently unrelated data are deconvoluted into generic mechanistic information integrating the combined influence of seeding, nucleation, growth, and fibril breakage events. It is notable that this complex assembly of interdependent events is ultimately reduced to a mathematically simple model, whose two parameters can be determined by little more than visual inspection. The good fitting results obtained for all cases confirm the CLM as a good approximation to the generalized underlying principle governing amyloid fibrillization. A perspective is presented on possible applications of the CLM during the development of new targets for amyloid disease therapeutics. This model is hosted on BioModels Database and identified by: BIOMD0000000531. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) and Gerstmann-Sträussler-Scheinker (GSS) disease, two genetically determined Prion protein (PrP) amyloidoses characterized by the deposition of PrP amyloid (APrP) in the vessel walls and in the cerebral parenchyma, respectively. A nonsense and a missense mutation in the PRNP gene lead to a premature termination of translation at codon position 160 (Q160Ter) of PrP in PrP-CAA, or to the substitution of an amino acid at residue 198 (F198S) of PrP in GSS. These two diseases have different clinical and pathologic phenotypes; however, in both diseases, neuropathologic analyses have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA and GSS are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA, Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA and GSS brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA and GSS are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.

Dataset Information

Masel2000 - Drugs to stop prion aggregates and other amyloids

Publications

Designing drugs to stop the formation of prion aggregates and other amyloids.

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