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Dissecting the Molecular Mechanisms of Motor Neurone Disease in Yeast and Worms

Peswani, Amber Rose (2015) Dissecting the Molecular Mechanisms of Motor Neurone Disease in Yeast and Worms. Master of Science by Research (MScRes) thesis, University of Kent.

Abstract

Superoxide dismutase 1 (SOD1) is an enzyme responsible for intracellular breakdown of toxic reactive oxygen species in prokaryotes and eukaryotes. Mutations in SOD1 are linked to the motor neurone disease Amyotrophic lateral sclerosis (ALS), with around 20% of familial (fALS) cases and, it is proposed, a significant proportion of sporadic cases caused by SOD1 mutations, however the mechanism of neuronal death remains unknown. Misfolding and aggregation of SOD1 leading to a ‘toxic gain of function’ is the most widely accepted mechanism, but further work is needed. To gain new insights into the underlying mechanism of cell toxicity, I am using two model systems: the yeast Saccharomyces cerevisiae and the nematode worm Caenorhabditis elegans. One hypothesis being tested was proposed by Ghadge et al. (2006) who reported that truncated forms of SOD1 (both wild type and fALS–linked mutants) form toxic aggregates in spinal cords of chick embryos, hypothesising that proteolytic digestion of unstable mutant SOD1 creates these toxic fragments. My project aims to elucidate how fALS–linked SOD1 mutants and SOD1 truncations exert toxicity on S. cerevisiae and C. elegans. In S. cerevisiae, SOD1 truncations do not specifically localise to, or disrupt the functioning of, mitochondria nor reduce viability of yeast although cell growth is slowed. Conversely, a motor-defective phenotype is exhibited in transgenic fALS–linked SOD1 mutant (G85R) C. elegans accompanied by vulval defects, which lead to reduced lifespan. My findings suggest that amino acid supplementation of G85R C. elegans mutants improves their motor function and vulval defects, implicating a role of amino acid signalling in mutant SOD1-mediated toxicity.

Item Type: Thesis (Master of Science by Research (MScRes))
Thesis advisor: Tuite, Mick
Thesis advisor: Gourlay, Campbell
Uncontrolled keywords: superoxide dismutase 1, amyotrophic lateral sclerosis, amino acid signalling, leucine
Subjects: Q Science > QD Chemistry > QD431 Organic Chemistry- Biochemistry- Proteins, peptides, amino acids
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Users 1 not found.
Date Deposited: 29 Sep 2015 11:00 UTC
Last Modified: 06 Feb 2020 04:13 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/50653 (The current URI for this page, for reference purposes)
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