Inherited neurodegenerative diseases: the one-hit model of neurodegeneration

The clinical manifestations of inherited neurodegenerative diseases are oft en delayed for periods from years to decades. This observation has led to t he idea that, in these disorders, neurons die from cumulative damage. A cri tical prediction of the cumulative damage hypothesis is that the probabilit y of neuronal death increases with age. However, we recently demonstrated, in 17 examples of neurodegeneration, that the kinetics of neuronal death ap pear to be exponential. These examples include both monogenic disorders, su ch as photoreceptor degenerations, as well as others that are partly or ent irely acquired (such as the clinical phase of parkinsonism and retinal deta chment). Exponential kinetics indicate that (i) the risk of death is consta nt, (ii) death occurs randomly in time and (iii) the death of each neuron i s independent of other neurons. We use the term 'one-hit model' to refer to the single catastrophic intracellular biochemical event, analogous to radi oactive decay, which leads to neuronal death in the diseases we analyzed. H ere, we examine the major features and implications of the one-hit model an d provide preliminary evidence that amyotrophic lateral sclerosis also appe ars to fit this model. We also discuss a testable biochemical hypothesis, t he mutant steady-state hypothesis, that we proposed to account for the one- hit model. Finally, we explore six unresolved issues that appear to challen ge this model. The one-hit model appears to capture a novel principle under lying many neurodegenerations. Our findings suggest that any consideration of the biochemical basis of neurodegeneration must include a meticulous exa mination of the kinetics of cell death.