Selectivity in MN Degeneration in Mouse Models of ALS
Rodent disease models are also useful in studies examining the selective vulnerability of specific MNs within an individual motor pool in ALS. Similar to human ALS, in mouse models based on mutant SOD1G93A, TDP-43A315T and FUSP525L, α-MNs selectively degenerate, while γ-MNs and MNs in the Onuf’s nucleus are spared (Mannen et al., 1977; Lalancette-Hebert et al., 2016). Also, as in ALS patients, the oculomotor MNs are spared in SOD1G93A (Niessen et al., 2006) and SOD1G86R (Nimchinsky et al., 2000) mice, whereas spinal cord MNs, trigeminal, facial and hypoglossal MNs are targeted (Niessen et al., 2006). In rNLS8 mice, MNs in the hypoglossal nucleus and the spinal cord are also involved, whereas those in the oculomotor, trigeminal, and facial nuclei are spared, despite widespread neuronal expression of cytoplasmic hTDP-43 (Spiller et al., 2016a). Atrophy of MNs in the trigeminal motor, facial and hypoglossal nuclei are also significantly smaller in TDP-43 knock-out mice, whereas MNs in the oculomotor nuclei are preserved (Iguchi et al., 2013). In addition, in another TDP-43 model, Prp-TDP43A315T mice, degeneration of specific neuronal populations occurs (Wegorzewska et al., 2009). Cytoplasmic ubiquitinated proteins accumulate in neurons of cortical layer V and in large neurons of the ventral horn and scattered interneurons, despite expression of the Prp-TDP-43A315T transgene in all neurons and glia (Wegorzewska et al., 2009). In a knock-in TDP-43 mouse model bearing a G298S mutation, MN loss was restricted to large-diameter α-MNs (Ebstein et al., 2019). Furthermore, in FUSP525L and FUSR521C mouse models, no significant MN loss was detected in oculomotor neurons, whereas spinal cord MNs were progressively lost during disease course (Sharma et al., 2016).
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.