Response to commentaries on forum position paper: The relevance of axonal swellings and atrophy to γ-diketone neurotoxicity

In the Forum, we suggest that the molecular mechanism of axonal atrophy is the primary pathogenic event in γ-diketone neuropathy, whereas swelling is of unclear significance. Several commentators have indicated that such a position is unfounded based on concerns regarding design and interpretation of our recently published work. However, in our responses to the commentators, we have attempted to address and clarify these issues. It is also important to remember that our findings are part of a larger body of supporting evidence that has been accumulating for over a decade. In addition to discussing axonal atrophy, a principle goal of the present Forum was to identify gaps in our understanding of γ-diketone axonopathy. Thus, while it had been assumed that swellings were pathognomonic, the issue is now complicated by the possible involvement of atrophy. Moreover, the impact of atrophy or swelling on axon function is unknown, and despite significant research, the respective molecular mechanism of each phenomenon has not been conclusively identified. Finally, critical information regarding the specificity of either atrophy or swelling is lacking; i.e., is the underlying mechanism and corresponding functional deficit sufficient to produce neurotoxicity, or is it a necessary step in a cascade of events leading to neuron dysfunction, or is the mechanism a non-specific consequence? In summary, although compelling evidence supports a role for atrophy, substantial work remains before the neurotoxicological significance of this effect and swelling can be deciphered. As the Forum and subsequent discussions indicate, γ-diketone neurotoxicity exhibits significant complexity at the molecular, cellular, functional and behavioral levels. Therefore, it is unlikely that either swelling or atrophy will be exclusively responsible for development of neurotoxicity.