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

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posted on 2022-03-28, 02:04 authored by Sonam Parakh
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.


Table of Contents

General introduction -- Chapter 2. Methods and materials -- Chapter 3. PDI is protective against major familial ALS causing proteins -- Chapter 4. Mechanism of action of PDI against mutant SOD1, TDP-43 and FUS in neuronal cells -- Chapter 5. Examining the role of PDI family members ERp57 and ERp72 in ALS -- Chapter 6. Cytoplasmic PDI is protective against mutant SOD1, TDP-43 and FUS in neuronal cell cultures -- Chapter 7. General discussion.


Theoretical thesis. Bibliography: pages 239-279

Awarding Institution

Macquarie University

Degree Type

Thesis PhD


PhD, Macquarie University, Faculty of Medicine and Health Sciences, Department of Biomedical Sciences

Department, Centre or School

Department of Biomedical Sciences

Year of Award


Principal Supervisor

Julie Atkin


Copyright Sonam Parakh 2015. Copyright disclaimer:




1 online resource (xvii, 309, [4] pages) illustrations (some colour)

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