There is evidence to support the prion-like model in ALS. The spread of neurodegeneration through adjacent anatomical regions of the CNS resembles the orderly spread of protein misfolding in prion disease. The in vitro cell-to-cell transmission of misfolded SOD1, TDP-43 and C9orf72 di-peptide repeat proteins has been demonstrated (Grad et al., 2011, 2014; Münch et al., 2011; Nonaka et al., 2013; Feiler et al., 2015; Porta et al., 2018). Similarly, the addition of cerebrospinal fluid from ALS/FTD patients (Ding et al., 2015), detergent-insoluble fractions of ALS-disease brains (Nonaka et al., 2013) or insoluble phosphorylated TDP-43 from post-mortem brain and spinal cord tissue (Smethurst et al., 2016), results in misfolding of TDP-43 when added to human cell lines. However, so far, only misfolded SOD1 and TDP-43 transmissibility has been demonstrated in vivo (Ayers et al., 2014, 2016; Porta et al., 2018). A recent study demonstrated that injection of brain-derived extracts from FTD patients into mice promoted the spatio-temporal transmission of TDP-43 pathology via the neuroanatomical connectome, suggesting that TDP-43 travels via axonal transport through connected regions of the CNS (Porta et al., 2018). Similarly, axonal transport is implicated in the spread of mutant SOD1 in mice (Ayers et al., 2016). Overexpression of misfolded TDP-43 or SOD1 facilitated the seeding ability of each inoculum, consistent with results obtained in vitro (Nonaka et al., 2013; Feiler et al., 2015; Smethurst et al., 2016).