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Title: Metabolomic studies of amyotrophic lateral sclerosis
Author: Valbuena, Gabriel
ISNI:       0000 0004 6420 9882
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive neurodegenerative disease, and is fatal within 3-5 years of onset. Metabolic dysfunctions have consistently been identified in ALS, although its role in pathogenesis remains unclear. In this thesis, I apply a metabolomic approach using 1H NMR spectroscopy and Gas Chromatography-Mass Spectrometry in a range of disease models of increasing biological complexity, as well as patient tissues, in order to reveal perturbations to the metabolic network that may impact the course of the disease. I examined alterations to metabolism in the motor neuron-like NSC-34 cell line, and found that mutant SOD1 led to increased glycolysis to divert glucose from oxidative metabolism, and a broad intracellular amino acid depletion. The contribution of non-cell autonomous processes were also investigated in an astrocyte-motor neuron co-culture model, where mutant SOD1 produced varying perturbations to glycolysis and oxidative stress responses in each cell type, together with decreased branched-chain amino acid catabolism and glutamine-glutamate production that may indicate impaired neurotransmitter recycling. I also found different metabolic responses to mutant SOD1 in two strains with varying rates of disease progression, suggesting a role for early metabolic responses to mutant SOD1 in affecting the course of disease. In addition, I identify a metabolic signature for C9ORF72 ALS in cerebellum tissue, providing evidence that the hexanucleotide repeat expansion leads to distinctive metabolic changes in the CNS. Overall, I demonstrate the applicability of metabolomics in ALS research, particularly in revealing hidden metabolic subtypes of the disease. This opens opportunities to improve our understanding of the processes leading to motor neuron death in ALS, and highlights the potential use of metabolomics as a tool to develop therapies targeted to the individual metabolic responses of individuals susceptible to ALS.
Supervisor: Keun, Hector ; Holmes, Elaine Sponsor: European Community
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral