page 75), who find that the aggregates of familial amyotrophic lateral sclerosis (fALS) are unusually porous compared to those of Huntington's disease (HD).
Both diseases are associated with the neuronal aggregation of a mutant protein in affected individuals. For fALS, the mutant protein is the free radical scavenger SOD1. The authors found that, unlike mutant htt, which forms a solid, impenetrable aggregate in HD, mutant SOD1 formed a honeycomb-like structure. YFP and other globular proteins were able to diffuse freely through cells containing SOD1 aggregates.
Certain proteins were not as free to come and go, however. These proteins might thus be the basis for cellular toxicity. The proteasome, a known interacting partner for many neurodegenerative disease–associated proteins, was trapped by the SOD1 aggregates, as it is by htt aggregates. Proteasomal activity was thus stymied.
Possibly due to this degradation impairment, SOD1 aggregates are generally thought to cause neuronal cell death. Some reports, however, have shown no correlation between the two. Matsumoto et al. believe that the contradictory findings stem from studying populations of cells, only a small percentage of which contain aggregates. Using live cell imaging, the authors were able to follow specifically those cells that formed aggregates. They found that 90% of them died soon after aggregate formation.If neuronal death in fALS indeed stems from the aggregates' sequestration of the proteasome, restoring proteasome activity to neurons might be a useful therapeutic strategy. But as different mutant proteins form unique aggregates, researchers should not assume that all aggregate-associated diseases can be treated the same. Aggregates of mutant ataxin-1, for instance, do not sequester the proteasome, suggesting that the same strategy might not counter spinocerebellar ataxia.