Role of protein disulphide isomerase and its family members in amyotrophic lateral sclerosis

Superoxide dismutase (SOD1), Tar-DNA binding protein-43 (TDP-43) and Fused in Sarcoma (FUS) are major proteins linked to Amyotrophic Lateral Sclerosis (ALS) pathology. Whilst neurodegenerative mechanisms are not fully defined in ALS, dysfunction to the Endoplasmic Reticulum (ER) is increasingly implicated in the pathology of the disease. Protein disulphide isomerase (PDI) is an ER chaperone which also functions as an isomerase and aids in the formation and reduction of protein disulphide bonds. It is primarily located in the ER but it is also found in other cellular locations. Our laboratory previously demonstrated that over-expression of PDI is protective against mutant SOD1 in neuronal cultures. PDI has also been shown to co-localise with FUS and TDP-43 positive inclusions in ALS patients. Here we examined whether over-expression of PDI is protective against mutant TDP-43 and FUS induced ER stress and ER-Golgi transport defects and mislocalisation into cytoplasm in cellular models. Furthermore, we examined the mechanism by which PDI is protective and suggests that the disulphide interchange activity is important for its protective function. Also PDI in the cytoplasm further accentuates its protective ability. Importantly, PDI was examined in vivo and it was demonstrated that a small molecule mimic of the PDI active site -1,2 bis (mercaptoacetamido) cyclohexane BMC reduced the loss of motor neuron in SOD1G93A mice signifying the relevance of PDI in disease pathology. The results in this study demonstrate that PDI is protective against the major misfolded proteins linked to ALS; therefore the molecular mimic may be a novel therapeutic target in multiple forms of ALS.