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

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Short description
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.

Format
SBML (L2V4)
Related Publication
  • A one-hit model of cell death in inherited neuronal degenerations.
  • Clarke G, Collins RA, Leavitt BR, Andrews DF, Hayden MR, Lumsden CJ, McInnes RR
  • Nature , 7/ 2000 , Volume 406 , pages: 195-199
  • Program in Developmental Biology, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
  • 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.
Contributors
Audald Lloret i Villas, administrator

Metadata information

is
BioModels Database MODEL1408070000
BioModels Database BIOMD0000000538
isDescribedBy
PubMed 10910361
hasTaxon
Taxonomy Homo sapiens
Taxonomy Mus musculus
Taxonomy Felis catus
Taxonomy Rattus norvegicus
Taxonomy Canis lupus familiaris
isVersionOf
Gene Ontology neuron apoptotic process
hasVersion
Human Disease Ontology retinal degeneration
Human Disease Ontology retinal disease
Human Disease Ontology retinal detachment
Human Disease Ontology Huntington's disease
Human Disease Ontology ocular albinism
Human Disease Ontology cerebral degeneration
Human Disease Ontology Parkinson's disease
Curation status
Curated
Name Description Size Actions

Model files

BIOMD0000000538_url.xml SBML L2V4 representation of Clarke2000 - One-hit model of cell death in neuronal degenerations 18.02 KB Preview | Download

Additional files

Clarke2000.cps Copasi file of the model 30.54 KB Preview | Download
BIOMD0000000538_urn.xml Auto-generated SBML file with URNs 17.75 KB Preview | Download
BIOMD0000000538-biopax3.owl Auto-generated BioPAX (Level 3) 8.30 KB Preview | Download
BIOMD0000000538.sci Auto-generated Scilab file 154.00 bytes Preview | Download
BIOMD0000000538.svg Auto-generated Reaction graph (SVG) 851.00 bytes Preview | Download
BIOMD0000000538.xpp Auto-generated XPP file 1.40 KB Preview | Download
BIOMD0000000538.vcml Auto-generated VCML file 900.00 bytes Preview | Download
BIOMD0000000538.pdf Auto-generated PDF file 129.13 KB Preview | Download
BIOMD0000000538-biopax2.owl Auto-generated BioPAX (Level 2) 7.67 KB Preview | Download
BIOMD0000000538.m Auto-generated Octave file 2.38 KB Preview | Download
BIOMD0000000538.png Auto-generated Reaction graph (PNG) 5.04 KB Preview | Download

  • Model originally submitted by : Audald Lloret i Villas
  • Submitted: Aug 7, 2014 11:54:59 AM
  • Last Modified: Dec 21, 2018 5:29:29 PM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Dec 21, 2018 5:29:29 PM
    • Submitted by: administrator
    • With comment: Include the additional files provided by the submitter in the original submission: Clarke2000.cps
  • Version: 2 public model Download this version
    • Submitted on: Sep 9, 2014 1:55:11 PM
    • Submitted by: Audald Lloret i Villas
    • With comment: Current version of Clarke2000 - One-hit model of cell death in neuronal degenerations
  • Version: 1 public model Download this version
    • Submitted on: Aug 7, 2014 11:54:59 AM
    • Submitted by: Audald Lloret i Villas
    • With comment: Original import of Clarke2000 - One-hit model of cell death in neuronal degenerations
Curator's comment:
(added: 07 Aug 2014, 13:59:50, updated: 07 Aug 2014, 13:59:50)
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.