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


ABSTRACT: 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: 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 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. This model is hosted on BioModels Database and identified by: BIOMD0000000538. 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): Retinal Degeneration,Retinal Detachment,Huntington's Disease,Retinal Disease,Ocular Albinism,Cerebral Degeneration,Parkinson's Disease

SUBMITTER: administrator  

PROVIDER: BIOMD0000000538 | BioModels | 2014-08-07

REPOSITORIES: BioModels

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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 20000701 6792


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. H  ...[more]

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