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dc.contributor.advisorGillingwater, Tom
dc.contributor.advisorParson, Simon
dc.contributor.authorMurray, Lyndsay M.
dc.date.accessioned2010-12-06T15:39:54Z
dc.date.available2010-12-06T15:39:54Z
dc.date.issued2010
dc.identifier.urihttp://hdl.handle.net/1842/4419
dc.description.abstractMounting evidence suggests that synaptic connections are early pathological targets in many neurodegenerative diseases, including motor neuron disease. A better understanding of synaptic pathology is therefore likely to be critical in order to develop effective therapeutic strategies. Spinal muscular atrophy (SMA) is a common autosomal recessive childhood form of motor neuron disease. Previous studies have highlighted nerve- and muscle-specific events in SMA, including atrophy of muscle fibres and postsynaptic motor endplates, loss of lower motor neuron cell bodies and denervation of neuromuscular junctions caused by loss of pre-synaptic inputs. Here I have undertaken a detailed morphological investigation of neuromuscular synaptic pathology in the Smn-/- ;SMN2 and Smn-/-;SMN2;Δ7 mouse models of SMA. Results imply that synaptic degeneration is an early and significant event in SMA, with progressive denervation and neurofilament accumulation being present at early symptomatic time points. I have identified selectively vulnerable motor units, which appear to conform to a distinct developmental subtype compared to more stable motor units. I have also identified significant postsynaptic atrophy which does no correlate with pre-synaptic denervation, suggesting that there is a requirement for Smn in both muscle and nerve and pathological events can occur in both tissues independently. Rigorous investigation of lower motor neuron development, connectivity and gene expression at pre-symptomatic time points revealed developmental abnormalities do not underlie neuromuscular vulnerability in SMA. Equivalent gene expression analysis at end-stage time points has implicated growth factor signalling and extracellular matrix integrity in SMA pathology. Using an alternative model of early onset neurodegeneration, I provide evidence that the processes regulating morphologically distinct types of synaptic degeneration are also mechanistically distinct. In summary, in this work I highlight the importance and incidence of synaptic pathology in mouse models of spinal muscular atrophy and provide mechanistic insight into the processes regulating neurodegeneration.en
dc.contributor.sponsorAnatomical Society of Great Britain and Irelanden
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionMurray LM, Comley LH, Thomson D, Parkinson N, Talbot K, Gillingwater TH. Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy. Hum Mol Genet. 2008; 17: 949-962.en
dc.relation.hasversionMurray LM, Thomson D, Conklin A, Wishart TM, Gillingwater TH. Loss of translation elongation factor (eEF1A2) expression in vivo differentiates between Wallerian degeneration and dying-back neuronal pathology. J Anat. 2008; 213: 633-645.en
dc.relation.hasversionSoriano FX, Baxter P, Murray LM, Sporn MB, Gillingwater TH, Hardingham GE. Transcriptional regulation of the AP-1 and Nrf2 target gene sulfiredoxin. Molecules and Cells. 2009; 27:279-282en
dc.subjectspinal muscular atrophyen
dc.subjectneuromuscular junctionen
dc.subjectNMJen
dc.subjectsynaptic vulnerabilityen
dc.subjectsynapseen
dc.titleSynaptic vulnerability in spinal muscular atrophyen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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