You are viewing a version of a model that has been updated. To access the latest version, and a more detailed display please go here.

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

  public model
Short description
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

Metadata information

Curation status
Curated
  • Model originally submitted by : Audald Lloret i Villas
  • Submitted: Aug 7, 2014 11:54:59 AM
  • Last Modified: Sep 9, 2014 1:55:11 PM
Revisions
  • 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.