Neuronal cells clogged with a mutant protein associated with amyotrophic lateral sclerosis (ALS) die within hours after clumps first form, researchers report.1 The finding directly links aggregation of malformed proteins with cell death characteristic of the disease, the authors claim.
By watching individual cells over the course of 48 hours, Richard Morimoto at Northwestern University and colleagues demonstrated that most cultured neurons die between 6 and 24 hours after mutant superoxide dismutase (SOD1) forms aggregates. Cells in which mutant SOD1 remains dispersed survive.
Morimoto suggests that the machinery for discarding misfolded proteins may have failed in some cells. Different cells may have different levels of chaperone molecules that escort unwanted molecules to the proteasome to be destroyed, he notes, and that may explain why mutated SOD1 aggregates in some cells but not others.
Steven Finkbeiner of the University of California in San Francisco – whose group demonstrated that aggregates can be protective in Huntington disease – says the methodology still leaves room for an alternative explanation. Greater or longer exposure to mutant SOD1 might be responsible for the cell death, he suggests, rather than the aggregates themselves. "It is unclear to me whether [the difference between the two studies] is due to differences in the extent to which expression levels were factored in or real differences in the underlying biology," he says.