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Title: Degeneration of the neuromuscular synaptic compartment in normal and Wlds mutant mice
Author: Gillingwater, Thomas Henry
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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Nerve section results in the rapid, Wallerian degeneration of distal axons and motor nerve terminals. This process is normally complete within 24-48 hours in wild-type rodents. By contrast, motor nerve terminals of the spontaneous mutant Wlds mouse persist, both functionally and morphologically, for up to two weeks following nerve injury. This thesis aims first, to extend knowledge and understanding of the fate of neuromuscular junctions (NMJ) in normal and Wlds mice following axotomy; second, to test the hypothesis that the Wlds phenotype is age-dependent; and third, to test the hypothesis that the Wlds phenotype is produced as a result of the expression of a Ube4b/Nmnat chimeric gene. Immunocytochemical, confocal and vital staining experiments revealed marked differences between the mechanisms of nerve terminal removal in axotomised wild-type and Wlds preparations. Wild-type preparations endured a rapid, fragmentary type of degeneration (the characteristics of classical Wallerian degeneration), whereas Wlds nerve terminals appeared to be withdrawn from endplates in a piecemeal fashion. Ultrastructural analysis confirmed that axotomised wild-type NMJs exhibited all of the classical signs of Wallerian degeneration, including in-situ nerve terminal fragmentation, mitochondrial swelling and lysis and phagocytosis by the terminal Schwann cell. Electron micrographs of axotomised Wlds NMJs demonstrated a retention of nerve terminal architecture, including synaptic vesicles and mitochondria. Together, these data suggest that when axonal degeneration is delayed, as in the Wlds mouse, a novel form of synaptic withdrawal is unmasked, and that aspects of this process resemble those which occur during the formation of mature innervation patterns in postnatal development. My studies provide evidence for a compartmental model of neurodegeneration. Whereas it is widely acknowledged that the somatic and axonal portions of a neuron have separate, compartmentalised mechanisms of degeneration, data presented here suggest that degeneration of synaptic terminals is also controlled by at least one other, independent mechanism, that is distinct from those found in the cell body and axon.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available