The concept of mutated SOD1 aggregate formation was previously evoked, but this article gives experimental evidence supporting this hypothesis. It remains now to explain why not all motoneurons (i.e. oculomotor nucleus) are not impaired.

View all comments by Roland Pochet

DiDonato and coworkers have studied the cysteine-independent aggregation of two FALS-associated SOD mutants, H43R and A4V. They found that both mutants have reduced stability (as found by guanidine-HCl denaturation) and activity with respect to the wild-type. Further, the pH-induced propensity of destabilized mutants to aggregate was probed by light scattering and the final fibrous aggregates were visualized by electron microscopy. It was found that the metal-free Apo-state of the enzyme was more prone to aggregation. These aggregates bound to Congo red and thioflavin T, indicating that the aggregates might have characteristic amyloid fibrils. However, a previous study (Stathopulos et al., 2003) of heat and TFE-induced aggregation shows that the binding is much weaker and the topology of in-vivo fibrils may be less ordered. Thus, aggregate morphologies may vary due to differences in the in-vitro conditions at which they are generated. The authors also found that the diameters of H43R fibrils were smaller than...  Read more

DiDonato and coworkers have studied the cysteine-independent aggregation of two FALS-associated SOD mutants, H43R and A4V. They found that both mutants have reduced stability (as found by guanidine-HCl denaturation) and activity with respect to the wild-type. Further, the pH-induced propensity of destabilized mutants to aggregate was probed by light scattering and the final fibrous aggregates were visualized by electron microscopy. It was found that the metal-free Apo-state of the enzyme was more prone to aggregation. These aggregates bound to Congo red and thioflavin T, indicating that the aggregates might have characteristic amyloid fibrils. However, a previous study (Stathopulos et al., 2003) of heat and TFE-induced aggregation shows that the binding is much weaker and the topology of in-vivo fibrils may be less ordered. Thus, aggregate morphologies may vary due to differences in the in-vitro conditions at which they are generated. The authors also found that the diameters of H43R fibrils were smaller than one native protein subunit, indicating that SOD possibly undergoes compaction before assembling into fibrils. The above observation is very interesting, given that proteins normally unfold/misfold (into expanded states) before aggregation, hinting at possible early events in SOD aggregation.

View all comments by Nikolay Dokholyan
View all comments by Sagar Khare