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

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.

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BIOMD0000000538.
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