TDP-43 is an ubiquitously expressed RNA-binding protein belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family. Fifty three mutations in TARDBP have now been associated with FALS, located within all but one reside of the C-terminal domain of TDP-43 [Gitcho et al., 2008; Kabashi et al., 2008; Van Deerlin et al., 2008; http://alsod.iop.kcl.ac.uk/]. Pathological forms of TDP-43 – phosphorylated, fragmented, aggregated, ubiquitinated TDP-43 – were identified as the major component of MN inclusions (Neumann et al., 2006) in almost all ALS cases, including SALS (97%) (Arai et al., 2006; Neumann et al., 2006; Mackenzie et al., 2007; Scotter et al., 2015; Le et al., 2016). TDP-43 pathology is also observed in C9orf72 mutation cases in several brain regions, including the frontal, temporal and primary motor cortices, hippocampus, basal ganglia, amygdala, thalamus and midbrain (Murray et al., 2011; Hsiung et al., 2012; Mahoney et al., 2012; Irwin et al., 2013; Mackenzie et al., 2013; Balendra and Isaacs, 2018), highlighting an important role for TDP-43 in neurodegeneration in both SALS and FALS. Moreover, ALS and FTD cases bearing TDP-43 pathology are often referred to “TDP-43 proteinopathies” (Mackenzie et al., 2009). TDP-43 shares similar functional roles in RNA-binding, splicing and nucleocytosolic RNA transport as FUS. Fifty nine mutations in FUS have been identified in both SALS and FALS patients (Lattante et al., 2013; http://alsod.iop.kcl.ac.uk/) and FUS colocalises with TDP-43 in protein aggregates in MNs of a proportion of SALS and FALS patients (Kwiatkowski et al., 2009; Deng et al., 2010).