12 Jul 2000

Do individual neurons gradually waste away in inherited neurodegenerative diseases, or are they functioning more or less normally until one catastrophic event does them in? A study published in tomorrow's Nature suggests that a "one-hit" hypothesis better explains the temporal pattern of cell death in a number of neurodegenerative disease models.

Despite the obvious biochemical differences in the etiology of various neurodegenerative disorders, it is has been suggested that common principles may apply in the death of neurons in these diseases. Prominent among these is the "cumulative-damage" hypothesis, which suggests that accumulation of toxic substances or of macromolecular damage gradually destroys individual neurons. But in their current paper, Roderick McInnes, Geoff Clarke, and colleagues at the University of Toronto present evidence supporting a model in which neurons in inherited disease exist in an abnormal steady state in which a rare catastrophic event will lead to cell death.

If the risk that an individual cell will die is increasing with time (as predicted by the cumulative-damage hypothesis), then a graphic representation of cell death in the population will be sigmoidal. On the other hand, if the risk that any individual cell will die is constant or decreases with time (per the one-hit hypothesis), the shape of the curve will be exponential. The authors examined experimental models of inherited neurodegenerative disease (including 12 different models of photoreceptor degeneration, as well as models of cerebellar degeneration, Parkinson's disease, and hippocampal neurons undergoing excitotoxic death), as well as an indirect measure of cell loss in living Huntington's disease patients. They concluded that the kinetics of neuronal loss was exponential in each case. "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," they write.

In addition to the implications such a model has for explaining causation in neurodegenerative disease, there are therapeutic implications. "The absence of cumulative damage means that the likelihood that a mutant neuron can be rescued by treatment is not diminished by age, although fewer cells will be available to rescue. Therefore, treatment at any stage of the illness is likely to confer benefit," write the authors.

In an accompanying News and Views letter, Nathaniel Heintz of the Rockefeller University in New York applauds the study, but notes that, "In some well-characterized animal models of neurological disease, obvious histological abnormalities appear and deterioration of neuronal function occurs well in advance of cell loss." Determining the relevance of the "one-hit" hypothesis to such processes will stimulate lively debate and much experimentation, he predicts.—Hakon Heimer