Commentary: Proteooxidotoxic process of aggregation

A recent editorial entitled "State of Aggregation" (Nat. Neurosci. 2011;14:399) described the importance of establishing the structural state of pathogenic protein aggregates (Aβ, α-synuclein, huntingtin, etc.) in studies of neurodegenerative disorders. While this is a laudable goal, it is based on the assumption that the neurotoxicity depends upon a specific tertiary structure of the protein aggregates. Here, I describe evidence (not mentioned in the editorial) that suggests that it is not the protein oligomers, per se, that damage neurons. Instead, neurons are damaged by an unseen sequence(s) of chemical reactions that generate reactive oxygen species (ROS), and it is the ROS that cause both protein aggregation and neurotoxicity. The latter "proteooxidotoxicity" mechanism provides an explanation for numerous findings in the field of neurodegenerative disorders, including the inability to identify specific receptors for the pathogenic proteins.