Macquarie University
01whole.pdf (39.32 MB)

Elucidating the cellular mechanisms associated with novel and known ALS genes

Download (39.32 MB)
posted on 2022-03-28, 21:29 authored by Sharlynn Shi Lin Wu
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease wherein both upper and lower motor neurons degenerate. As the only proven cause of ALS, gene mutations not only inform diagnostic testing but also implicate disease mechanisms that underlie ALS and guide the development of cell and animal models and therapeutics. A novel gene discovery strategy prioritised two candidate genes, VPS29 and ACACB,from an Australian ALS family that was negative for known ALS mutations. This thesis sought to evaluate the pathogenicity of both candidate genes. This study found that ACACB p.I619T mislocalised and displayed increased colocalisation with TDP-43 as compared to wild-type, consistent with known cellular ALS pathology. Preliminary observations revealed that the co-expression of ACACB p.I619T with the top-ranking candidate variant VPS29 p.P70L resulted in exacerbated cellular ALS-like pathology. Proteomic analyses of cells expressing these two candidate variants suggested that pro-apoptotic PTEN and death receptor signaling pathways were dysregulated. A preliminary histopathological assessment of known ALS gene GLE1 in patient spinal cord tissue was performed to reveal whether GLE1-associated mechanisms are perturbed in ALS. Preliminary staining revealed GLE1-positive inclusion-like structures in sporadic ALS motor neurons. Overall, this study investigated the pathogenic roles of novel and known ALS genes to assess the mechanism underlying ALS pathogenesis to improve our understanding of ALS biology.


Table of Contents

1. Introduction -- 2. Materials -- 3. Methods -- 4. Results -- 5. Discussion -- Appendix -- Ethics approval -- References.


Empirical thesis. Bibliography: pages 127-149

Awarding Institution

Macquarie University

Degree Type

Thesis MRes


MRes, 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

Shu Yang


Copyright Sharlynn Shi Lin Wu 2019. Copyright disclaimer:




1 online resource (xvi, 149 pages) colour illustrations

Former Identifiers