Defective nucleocytoplasmic transport is emerging as an important cellular mechanism in the initiation or progression of ALS. Nuclear pore pathology is present in the brain of SALS and C9orf72 patients (Zhang K. et al., 2015; Chou et al., 2018). C9orf72 repeat expansions impair protein trafficking from the cytoplasm to the nucleus, and reduce the proportion of nuclear TDP-43 in patient-derived MNs (Zhang K. et al., 2015), thereby mimicking the nuclear depletion of TDP-43 in ALS patients (Neumann et al., 2006). Proteins involved in nucleocytoplasmic transport are abnormally localized in aggregates in the cortex of C9orf72 ALS patients, patient-derived MNs and the brain of C9orf72 mouse models (Zhang K. et al., 2015, Zhang et al., 2016). Similarly, TDP-43 pathology disrupts nuclear pore complexes and lamina morphology in cell lines and patient-derived MNs. Furthermore, insoluble TDP-43 aggregates also contain components of the nucleocytoplasmic machinery (Chou et al., 2018). Both protein import and RNA export were impaired by mutant TDP-43 in the brain of SALS mouse primary neurons (Chou et al., 2018). A recent meta-analysis of ALS modifier genes identified several genes encoding proteins involved in nucleocytoplasmic shuttling (Yanagi et al., 2019). In fact, the most enriched gene ontology term in this study was “protein import into the nucleus,” and it included KPNB1, encoding importin subunit beta-1, which was identified as a genetic modifier in three separate ALS models. Interestingly, the gene encoding lamin B1 subunit 1, which is involved in nuclear stability, was upregulated in oculomotor neurons compared to hypoglossal MNs and spinal cord MNs (Hedlund et al., 2010). Furthermore, lamin B1 is also known to possess cellular protective functions such as controlling the cellular response to oxidative stress (Malhas et al., 2009), DNA repair (Butin-Israeli et al., 2015) and RNA synthesis (Tang et al., 2008). It is therefore tempting to speculate that lamin B1 confers resistance to specific MN populations when highly expressed. However, further work is necessary to examine this possibility.