Abstract:
:The clinical manifestations of inherited neurodegenerative diseases are often delayed for periods from years to decades. This observation has led to the idea that, in these disorders, neurons die from cumulative damage. A critical prediction of the cumulative damage hypothesis is that the probability of neuronal death increases with age. However, we recently demonstrated, in 17 examples of neurodegeneration, that the kinetics of neuronal death appear to be exponential. These examples include both monogenic disorders, such as photoreceptor degenerations, as well as others that are partly or entirely acquired (such as the clinical phase of parkinsonism and retinal detachment). Exponential kinetics indicate that (i) the risk of death is constant, (ii) death occurs randomly in time and (iii) the death of each neuron is independent of other neurons. We use the term 'one-hit model' to refer to the single catastrophic intracellular biochemical event, analogous to radioactive decay, which leads to neuronal death in the diseases we analyzed. Here, we examine the major features and implications of the one-hit model and provide preliminary evidence that amyotrophic lateral sclerosis also appears to fit this model. We also discuss a testable biochemical hypothesis, the mutant steady-state hypothesis, that we proposed to account for the one-hit model. Finally, we explore six unresolved issues that appear to challenge this model. The one-hit model appears to capture a novel principle underlying many neurodegenerations. Our findings suggest that any consideration of the biochemical basis of neurodegeneration must include a meticulous examination of the kinetics of cell death.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Clarke G,Lumsden CJ,McInnes RRdoi
10.1093/hmg/10.20.2269subject
Has Abstractpub_date
2001-10-01 00:00:00pages
2269-75issue
20eissn
0964-6906issn
1460-2083journal_volume
10pub_type
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