Macquarie University
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The protective mechanisms of protein disulphide isomerase in amyotrophic lateral sclerosis

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posted on 2022-03-28, 23:48 authored by Emma Renee Perri
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterised by the degeneration of motor neurons. Numerous genes are linked to ALS both genetically and pathologically. Approximately 10% of ALS cases are familial, and of these cases, approximately 20% are due to mutations in the gene encoding superoxide dismutase 1 (SOD1), and approximately 10% are due to mutations in TAR DNA binding protein 43 (TDP-43) and fused in sarcoma (FUS). A major hallmark observed in ALS is the accumulation of misfolded proteins, containing either SOD1, TDP-43 and FUS, which form aggregates in the cytoplasm of degenerating motor neurons. However, the pathogenic mechanisms of disease in ALS remain poorly understood. Recent evidence suggests that dysfunction to the Endoplasmic Reticulum (ER), resulting in ER stress, is increasingly implicated in ALS pathogenesis. Protein Disulphide Isomerase (PDI) is an ER chaperone which functions as an oxidoreductase, utilising its disulphide interchange activity to oxidise, reduce and isomerase disulphide bonds. Our laboratory has previously demonstrated that PDI overexpression is protective against mutant SOD1, TDP-43 and FUS in neuronal cell cultures. Hence, here we examined that PDI overexpression is also protective against ALS mechanisms of pathogenesis triggered by mutant forms of novel ALS protein, Cyclin F. Previous studies have also identified that PDI's disulphide interchange activity is fundamental for its protective activity. Therefore, here we further investigated the properties of PDI which are important in mediating this activity. Results obtained suggest that PDI's a domain is essential for PDI's protective function, as well as its oxidase activity (capability to form disulphide bonds). These properties were verified in cell culture models expressing mutant FUS. Ultimately, there is a need for more effective therapeutics in ALS, thus, peptides mimicking PDI's a domain and oxidase activity were developed and analysed here for their protective effect in ALS cell models.


Table of Contents

Chapter 1. General introductionn -- Chapter 2. Material and methods -- Chapter 3. PDI is protective against ALS-associated mutant cyclin F expressed in neuronal cells -- Chapter 4. Characterising the protective properties of PDI against misfolded proteins in ALS -- Chapter 5. The role of redox activity in the protective function of PDI -- Chapter 6. The role of PDI and its redox activity in FUS-linked ALS -- Chapter 7. Peptides based on PDI's active site are protective in neuronal cells expressing mutant SOD1 -- Chapter 8. General discussion -- References -- Appendices.


Empirical thesis. Bibliography: pages 566-598

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 Emma Renee Perri 2017. Copyright disclaimer:




1 online resource (xxii, 607 pages) colour illustrations

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