La Trobe
DOCUMENT
38169_SOURCE01_4_A.pdf (9.75 MB)
ARCHIVE
38169_SOURCE03_3_A.zip (6.33 MB)
1/0
2 files

Cellular trafficking disruption in amyotrophic lateral sclerosis

thesis
posted on 2023-01-18, 17:57 authored by Vinod Sundaramoorthy
Submission note: A thesis submitted in total fulfilment of the requirements for the degree of Doctor of Philosophy to the Department of Biochemistry, Institute of Molecular Science, La Trobe University, Bundoora.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which causes degeneration and death of motor neurons. Currently there is no effective treatment and understanding the cellular and molecular mechanisms of neurodegeneration is essential for designing an effective therapeutic strategy. Several distinct pathological mechanisms are associated with motor neuron death, but the link between these mechanisms remains unclear. ALS begins in a focal region and appears to spread contiguously throughout the motor neurons in the brain, brain stem and spinal cord, and it remains unclear how the spread of pathology is mediated. Another interesting feature of ALS is that motor neurons are specifically targeted by ubiquitously expressed pathogenic proteins. Disruption of intracellular trafficking processes is one mechanism associated with neurodegeneration in ALS, and this may underlie the specific vulnerability of motor neurons, which have large cell bodies and long axons. The overall aim of this thesis was to examine the role of disruption to intracellular trafficking in neurodegeneration in ALS. The thesis firstly presents an already published study, which demonstrates that uptake of extracellular misfolded wildtype or mutant superoxide dismutase 1 (SOD1) disrupts trafficking from the Endoplasmic reticulum (ER) to Golgi apparatus, induces Golgi fragmentation, ER stress and triggers apoptotic cell death in neuronal cells, providing novel insights into pathogenic mechanisms linked to the ER-Golgi compartments and the mechanism of spread of neurodegeneration in ALS. In the second study (currently under peer review), mechanisms of neurodegeneration linked to optineurin were investigated. Optineurin interacts with the molecular motor myosin VI and it was demonstrated here that this interaction is impaired in both sporadic and familial ALS. This leads to inhibition of optineurin-myosin VI mediated cellular trafficking and autophagy, thus describing novel insights into the pathology induced by optineurin in ALS. This thesis also examines a novel protein associated with ALS. Mutations in CCNF, which encodes a E3 ubiquitin ligase; cyclin F were recently described in familial ALS and expression of this mutant in neuronal cells induced ER stress, recruitment to stress granules and apoptosis. Finally this thesis examines the normal cellular function of C9orf72 (chromosome 9 open reading frame 72), which is associated with most cases of familial ALS. Depletion of C9orf72 led to impairment of endocytosis and autophagy, implying that the normal function of C9orf72 is related to cellular trafficking. In conclusion this thesis provides further evidence that disruption of cellular trafficking processes trigger neurodegeneration in ALS.

History

Center or Department

Institute of Molecular Science. Department of Biochemistry.

Thesis type

  • Ph. D.

Awarding institution

La Trobe University

Year Awarded

2015

Rights Statement

This thesis contains third party copyright material which has been reproduced here with permission. Any further use requires permission of the copyright owner. The thesis author retains all proprietary rights (such as copyright and patent rights) over all other content of this thesis, and has granted La Trobe University permission to reproduce and communicate this version of the thesis. The author has declared that any third party copyright material contained within the thesis made available here is reproduced and communicated with permission. If you believe that any material has been made available without permission of the copyright owner please contact us with the details.

Data source

arrow migration 2023-01-10 00:15. Ref: latrobe:38169 (9e0739)

Usage metrics

    Open Theses

    Categories

    No categories selected

    Keywords

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC