New Model for Neuronal Cell Death in Inherited Neurodegerative Diseases


There appear to be different biochemical mechanisms that underlie neuro-degeneration in a variety of different diseases including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) and amyotrophic lateral sclerosis (ALS). AD, PD and HD, are all characterized by the accumulation of protein aggregates, although the genes that produce the offending proteins are different, whereas in ALS there are alterations in the morphology of neuronal axons and in the expression of genes that encode neurofilaments.

A study that was recently published in the journal Nature suggests that although the essential biochemistry of these diseases may be different, they may have a common mechanism of neuronal cell death. Previously it was postulated that this common mechanism may be the process known as the 'cumulative-damage' hypothesis, which holds that the accumulation of damage to macromolecules, or toxic substances, eventually leads to the demise of the affected neuronal population. Over time, this would lead to an increase in the probability that a cell will die. If this theory were incorrect, one would expect that the probability of cell death would either remain constant, or would decline.

Clarke et al. investigated the kinetics of neuronal death in several neuro-degenerative diseases, in an effort to test the cumulative-damage hypothesis. Twelve different models of photoreceptor degeneration, hippocampal neurons undergoing excitotoxic cell death, and mouse models of cerebellar degeneration and Parkinson's and Huntington's disease, all showed patterns of death that are more consistent with a mathematical model in which the risk of cell death remains constant, or decreases exponentially with age. The authors propose that affected neurons are in an abnormal state, which they refer to as a 'mutant steady state', in which there is an increase in the probability that a single, rare catastrophic event will lead to cell death.

Particularly important is the fact that this study has implications for therapeutic intervention. The fact that a cell is not necessarily more likely to die with increasing age suggests that it may still be rescued by pharmaceutical intervention, even at a late stage in the disease process.


  1. Clarke G. et al. Nature 2000, 406:195-199.