In mutant SOD1G93A mice, FF α-MNs are more susceptible to degenerate than FR α-MNs, resulting in the FF muscles becoming paralyzed before FR muscles (Hegedus et al., 2007). Furthermore, tonic S-units only disconnect from the muscle at disease end stage, meaning that S α-MNs are the least vulnerable within motor pools in SOD1G93A, SOD1G85R (Frey et al., 2000; Pun et al., 2006; Hegedus et al., 2007; Hadzipasic et al., 2014), TDP-43 rNLS8 (Spiller et al., 2016a), FUSR521C and FUSP525L transgenic models (Sharma et al., 2016). These findings together therefore provide strong evidence that there is a gradient of vulnerability amongst spinal MNs, whereby the faster, less excitable motor units are affected before the slower, more excitable types, at least in mouse models. Interestingly, selective denervation of MN subtypes occurs at the NMJ. Less denervation of the relatively resistant slow-twitch soleus muscle (Frey et al., 2000), compared to the vulnerable fast-twitch tibialis anterior muscle, occurs in TDP-43M337V, TDP-43G298S, FUSP525L, FUSR521C and TDP-43 rNLS8 mouse models (Sharma et al., 2016; Spiller et al., 2016a; Ebstein et al., 2019). In both the low- and high-copy s-SOD1G93A and SOD1G93A mice, the onset of interneuron degeneration also precedes the onset of behavioral motor manifestations and most MN degeneration (Chang and Martin, 2009; Jiang et al., 2009; Pullen and Athanasiou, 2009). Subtle changes to inhibitory synaptic inputs to MNs may therefore modulate MN excitability, leading to degeneration and motor symptoms in ALS/FTD.