There is now little doubt that the prime cause of the motor-neuron disease amyotrophic lateral sclerosis (ALS) is related to misfolding and aggregation of the metalloenzyme Cu/Zn superoxide dismutase (SOD1). Yet, SOD1 has turned out remarkably resistant to aggregation under physiological conditions in vitro. Pathologic mutant proteins that are destabilized to the extent that they fail to fold can still be stored at room temperature for long periods of time without notable signs of self-association. To produce SOD1 aggregates one has to resort to more radical measures, such as high temperature at low pH (1, 2), organic solvents (1), or oxidative cross-linking of the protein's solvent-accessible cysteines (3). Because these conditions are different from those in the cell the connection between SOD1 aggregation and ALS has remained elusive; after all, most if not all proteins contain sequences capable of nucleating aggregation (4) and can thus be forced to aggregate in vitro if the conditions are made sufficiently "persuasive." In this issue of PNAS, Valentine and collaborators (5) present a new interesting piece to the puzzle by showing that SOD1 can be made to aggregate under conditions that are physiologically relevant. The trick seems to be simply that the solution requires appropriate agitation. After a few hours of this treatment in an orbital shaker at 250 rpm, immature molecules of wild-type SOD1 nucleate into ordered fibrillar structures similar to those observed in classical amyloidoses such as Alzheimer's and Huntington's diseases. For nucleation to occur, however, the protein also needs to be demetallated and without its stabilizing disulfide bridge. Once the seeds are formed the process can recruit more stable SOD1 species for the fibril elongation. Similar results were published independently by Furukawa et al. (6) just a few months ago.
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