Fig. 5 |. An axon vulnerability spectrum in humans and mice.

The figure shows the range of known axon survival phenotypes in mice and proposed analogous phenotypes in the human population for which evidence is growing. The line graph depicts the likely prevalence in the human population and the gradients underneath depict protein and enzyme activity levels of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and sterile-α and Toll/interleukin 1 receptor (TIR) motif containing protein 1 (SARM1) in axons. The pink and blue boxes show five distinct phenotypes in humans and mice, respectively, all of which have been extensively characterized in mice^6,13,105. In humans, the first two phenotypes (non-viable and pathogenic) have been linked to NMNAT2 mutation^89,90. Causes of the proposed disease-modifying effects indicated towards the right side, corresponding to lower axon vulnerability, may include (1) SARM1 splicing alleles that are present in the Genome Aggregation Database (gnomAD), which are likely to disrupt the function of this pro-degeneration protein and (2) higher than average expression levels of NMNAT2⁹⁵, which are likely to result in gain of function of this pro-survival protein.