Matrix Metalloproteinase (MMP9) has been recently identified as another determinant of selective neuronal vulnerability in SOD1G93A mice (Kaplan et al., 2014). MMP-9 was strongly expressed by vulnerable FR spinal MNs, but not oculomotor, Onuf’s nuclei or S α-MNs, and it enhanced ER stress and mediated muscle denervation in this model (Kaplan et al., 2014). Delivery of MMP-9 into FF-MNs, but not in oculomotor neurons, accelerates denervation in SOD1G93A mice (Kaplan et al., 2014). Similarly, another study demonstrated that reduction of MMP-9 expression attenuated neuromuscular defects in rNLS8 mice expressing cytoplasmic hTDP43ΔNLS in neurons (Spiller et al., 2019). Edaravone, a free radical scavenger which inhibits MMP-9 expression, was recently approved for the treatment of ALS in Japan, South Korea, United States and Canada (Yoshino and Kimura, 2006; Ito et al., 2008; Yagi et al., 2009). Further molecular investigations into the differences and similarities between different motor units in ALS should yield additional insights into their vulnerability to neurodegeneration.