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Title: In vitro studies on AMPA receptor-mediated motor neuron death : relevance for Amyotropic Lateral Sclerosis
Author: De Paola, Massimiliano
Awarding Body: The Open University
Current Institution: Open University
Date of Award: 2008
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Amyotrophic Lateral Sclerosis ALS is a desolating neurological disease mainly characterized by progressive motor neuron degeneration, muscle atrophy up to premature death. It is not yet fully understood in terms of etiology and, as a consequence, it is still orphan of cures. This project was aimed at studying some of the main creditable causal events leading to motor neuron degeneration in ALS, ie. AMPAR-dependent excitotoxicity, neuroinflammation, intracellular protein aggregation.1 We investigated the intracellular mechanisms that are induced in motor neurons by AMPARmediated excitotoxicity, demonstrating that different death pathways were activated depending on the intensity of the initial stimulus to the receptor. Low AMPAR agonist concentrations induce, indeed, the typical intracellular events of the apoptotic pathway, while higher concentrations trigger to non-apoptotic motor neuron death. 2 We analysed the intracellular effect of mediators of the inflammatory signalling, ie. TNF-α and IL-8, and their interaction with the AMPAR-dependent excitotoxic pathway. We demonstrated that IL-8-induced motor neuron death is specifically mediated by the CXCR2 chemokine receptor. TNFa exerts both neurotoxic effect and neuroprotection against AMPAR-mediated toxicity dntly on the presence of mature and active glial cells. 3 We studied the effect of intracellular α-synuclein accumulation in motor neurons, revealing a dual concentration-dependen effect since micromolar protein concentrations are neurotoxic, while nanoDmolar concentrations induce neuroprotective effect against oxidative insults. In hght of such results, we tested the effectiveness of potentially neuroprotective drugs which could interfere with the intracellular death mechanisms of motor neurons. We found that Erythropoietin (EPO) and different non-erythropoietic EPO derivatives (CEPO, ASIALOEPO and HBP) have specific neuroprotective properties against the apoptotic AMPAR-dependent death pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available