Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects the upper and lower motor neurons of the brain stem and spinal cord. It causes muscle weakness and paralysis and patients die due to respiratory failure within 3-5 years after diagnosis. The key hallmarks of ALS are protein misfolding, formation of abnormal protein inclusions, ER stress, oxidative stress and defects in axonal transport; however, the exact molecular mechanisms that trigger neurodegeneration in ALS is unknown. Superoxide dismutase (SOD1), Fused in Sarcoma (FUS) and Tar-DNA binding protein-43 (TDP-43) are linked to ALS genetically and pathologically. Recently, dysfunction to the Endoplasmic Reticulum (ER) has been increasingly implicated in ALS pathology and it is observed early in disease. Protein disulphide isomerase (PDI) is a chaperone induced during ER stress which also functions as disulphide isomerase in the formation and reduction of protein disulphide bonds. PDI is primarily located in the ER but it is also found in other cellular locations. Our laboratory previously showed that over-expression of PDI is protective against mutant SOD1-induced ER stress and toxicity and that PDI co-localizes with FUS and TDP-43 positive inclusions in ALS patients. Here we examined whether over-expression of PDI is also protective against FUS and TDP-43 cellular pathology and the mechanism by which this occurs. PDI was found to be protective against both TDP-43 and FUS-induced cellular pathology and this protection involved the disulphide interchange activity. A small molecule mimic of the PDI active site BMC, was also examined in-vivo in animal models of ALS (transgenic SOD1G93A mice). BMC was found to rescue motor neuron loss in these animals, implying that it may have potential as a novel therapeutic in ALS. Hence in summary we show that PDI is protective against multiple misfolded proteins linked pathologically to ALS, suggesting that it may have broad therapeutic efficacy in the diverse forms of ALS.