Heterogeneous cellular environments modulate one-hit neuronal death kinetics

Abstract We recently demonstrated that cell loss kinetics in diverse forms of neurodegeneration (ND) suggests a universal death switch mechanism in which each cell is at a constant risk to initiate apoptosis. We proposed that mutant and injured neurons exist in a viable state typified by an increased risk of initiating death processes [Clarke, Collins, Leavitt, Andrews, Hayden, Lumsden, McInnes, A one-hit model of cell death in inherited neuronal degenerations, Nature 406 (2000) 195–199]. To date, however, measurements of cell death risk have been available only as averages across the affected cell population. Here we develop and apply a method of death kinetic analysis in which the risk factors vary across the neuronal population, as for example due to regional heterogeneities in the cellular microenvironment. We find that most cases of ND for which cell loss data has been obtained are better explained by death risks that vary from cell to cell, compared to death risk that is constant across the neuronal population. Strikingly, a common form of the frequency distribution defining the death risk heterogeneity is shared across most of these cases. This first characterization of the kinetic heterogeneity in one-hit neuronal death, therefore, suggests that the wide variety of ND now known may share mechanisms through which regional differences in the cellular microenvironment modulate the kinetics of cell loss.