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BIOMD0000000538 - Clarke2000 - One-hit model of cell death in neuronal degenerations

 

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Reference Publication
Publication ID: 10910361
Clarke G, Collins RA, Leavitt BR, Andrews DF, Hayden MR, Lumsden CJ, McInnes RR.
A one-hit model of cell death in inherited neuronal degenerations.
Nature 2000 Jul; 406(6792): 195-199
Program in Developmental Biology, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.  [more]
Model
Original Model: BIOMD0000000538.origin
Submitter: Audald Lloret i Villas
Submission ID: MODEL1408070000
Submission Date: 07 Aug 2014 11:54:59 UTC
Last Modification Date: 09 Sep 2014 13:55:11 UTC
Creation Date: 07 Aug 2014 12:59:06 UTC
Encoders:  Audald Lloret i Villas
set #1
bqbiol:hasVersion Human Disease Ontology Huntington's disease
Human Disease Ontology DOID:14330
Human Disease Ontology ocular albinism
Human Disease Ontology retinal disease
Human Disease Ontology retinal detachment
Human Disease Ontology cerebral degeneration
Human Disease Ontology retinal degeneration
set #2
bqbiol:hasTaxon Taxonomy Rattus norvegicus
Taxonomy Canis lupus familiaris
Taxonomy Felis catus
Taxonomy Mus musculus
Taxonomy Homo sapiens
set #3
bqbiol:isVersionOf Gene Ontology neuron apoptotic process
Notes
Clarke2000 - One-hit model of cell death in neuronal degenerations
This one-hit model fits different neuronal-death associated diseases for different animal models. 

This model is described in the article:

Clarke G, Collins RA, Leavitt BR, Andrews DF, Hayden MR, Lumsden CJ, McInnes RR.
Nature 2000 Jul; 406(6792): 195-199

Abstract:

In genetic disorders associated with premature neuronal death, symptoms may not appear for years or decades. This delay in clinical onset is often assumed to reflect the occurrence of age-dependent cumulative damage. For example, it has been suggested that oxidative stress disrupts metabolism in neurological degenerative disorders by the cumulative damage of essential macromolecules. A prediction of the cumulative damage hypothesis is that the probability of cell death will increase over time. Here we show in contrast that the kinetics of neuronal death in 12 models of photoreceptor degeneration, hippocampal neurons undergoing excitotoxic cell death, a mouse model of cerebellar degeneration and Parkinson's and Huntington's diseases are all exponential and better explained by mathematical models in which the risk of cell death remains constant or decreases exponentially with age. These kinetics argue against the cumulative damage hypothesis; instead, the time of death of any neuron is random. Our findings are most simply accommodated by a 'one-hit' biochemical model in which mutation imposes a mutant steady state on the neuron and a single event randomly initiates cell death. This model appears to be common to many forms of neurodegeneration and has implications for therapeutic strategies.

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.

Model
Publication ID: 10910361 Submission Date: 07 Aug 2014 11:54:59 UTC Last Modification Date: 09 Sep 2014 13:55:11 UTC Creation Date: 07 Aug 2014 12:59:06 UTC
Mathematical expressions
Rules
Assignment Rule (variable: ONLrom) Rate Rule (variable: ONLnr) Rate Rule (variable: ONLpcd)  
Physical entities
Compartments Species
Brain ONLnr ONLpcd ONLrom
Global parameters
Munr Mupcd Rrom ONLrom
Murom      
Reactions (0)
Rules (3)
 
 Assignment Rule (name: ONLrom) ONLrom = ONLrom_0*exp((exp((-Rrom)*time)-1)*Murom/Rrom)*100/ONLrom_0
 
 Rate Rule (name: ONLnr) d [ ONLnr] / d t= (-Munr)*ONLnr
 
 Rate Rule (name: ONLpcd) d [ ONLpcd] / d t= (-Mupcd)*ONLpcd
 
 Brain Spatial dimensions: 3.0  Compartment size: 1.0
 
 ONLnr
Compartment: Brain
Initial concentration: 100.0
 
 ONLpcd
Compartment: Brain
Initial concentration: 100.0
 
  ONLrom
Compartment: Brain
Initial concentration: 100.0
 
Global Parameters (5)
 
 Munr
Value: 0.278
Constant
 
 Mupcd
Value: 0.223
Constant
 
 Rrom
Value: 0.103
Constant
 
 ONLrom
Value: 40.947
Constant
 
 Murom
Value: 0.0708
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000538

Curator's comment: (updated: 07 Aug 2014 13:59:50 GMT)

Figures 1C (pcd/pcd mice and nr/nr mice models) and 2A (Rom1-/- mice model) have been reproduced here. Evolution of outer nuclear layer (ONL) thickness during 12 months.

- pcd/pcd and nr/nr mice models are plotted by using constant risk of cell death, according to the article.
- Rom1-/- mice mode is plotted by using exponentially decreasing risk of cell death, according to the supplementary information.

The simulation was done using Copasi v4.12 (Build 81) and the plots were generated using Gnuplot. The Copasi file of the model with simulation settings can be downloaded from the below link.

Additional file(s)
  • Clarke2000 - One-hit model of cell death in neuronal degenerations:
    Copasi file of the model
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