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A one-hit model of cell death in inherited neuronal degenerations

Nature volume 406, pages 195–199 (2000)Cite this article

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 damage1,2,3,4,5,6. For example, it has been suggested that oxidative stress disrupts metabolism in neurological degenerative disorders by the cumulative damage of essential macromolecules1,4,7. 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 death8, a mouse model of cerebellar degeneration9 and Parkinson's10 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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Figure 1: Animal models of inherited photoreceptor degeneration and retinal detachment, in which the kinetics of cell death are best described by a constant risk of neuronal death (see equations (1) and (3) in Methods).
Figure 2: Animal models of inherited photoreceptor degeneration in which the kinetics of cell death are best described by an exponentially decreasing risk of death (see equations 1 and 2 in Methods).
Figure 3: Examples of non-retinal neuronal death that display a constant or exponentially decreasing risk of death.
Figure 4: The exponential kinetics of cell death in inherited neuronal degenerations suggest the existence of a mutant steady state (MSS) in which the risk of cell death is increased.

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Acknowledgements

We thank the physicians of the Huntington's disease patients for their help and support of this study; M. LaVail for sharing unpublished data on P23H rhodopsin-expressing transgenic rats; and A. G. Kundson Jr, T. P. Dryja, D. J. Zack, H. Lipshitz, M. W. Salter and S. Meyn for critical reading of the manuscript. This work was supported by grants from the Foundation Fighting Blindness (R.R.M.), The Macular Vision Research Foundation (R.R.M.), The RP Eye Research Foundation of Canada (R.R.M.), MRC of Canada (M.R.H. and B.R.L.), the Canadian Genetic Disease Network (R.R.M. and M.R.H.) and the Huntington Disease Society of America (M.R.H.). M.R.H. is an Established Investigator of the BC Children's Hospital. R.R.M. is an International Research Scholar of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Programs in Developmental Biology and Genetics, The Research Institute, Hospital for Sick Children, 555 University Ave., Toronto, M5G 1X8, Ontario, Canada

    Geoff Clarke & Roderick R. McInnes

  2. Departments of Molecular and Medical Genetics,

    Geoff Clarke, Richard A. Collins & Roderick R. McInnes

  3. Pediatrics,

    Roderick R. McInnes

  4. Department of Medicine, Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, M5S 1A8, Ontario, Canada

    Charles J. Lumsden & Roderick R. McInnes

  5. Department of Medical Genetics University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, V5Z 4H4, British Columbia, Canada

    Blair R. Leavitt & Michael R. Hayden

  6. Department of Statistics, University of Toronto, 100 St. George Street, M5S 3G3, Canada

    David F. Andrews

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Clarke, G., Collins, R., Leavitt, B. et al. A one-hit model of cell death in inherited neuronal degenerations. Nature 406, 195–199 (2000). https://doi.org/10.1038/35018098

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