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dc.creatorBusch, David James
dc.date.accessioned2012-10-03T21:32:33Z
dc.date.available2012-10-03T21:32:33Z
dc.date.created2012-08
dc.date.issued2012-10-03
dc.date.submittedAugust 2012
dc.identifier.urihttp://hdl.handle.net/2152/ETD-UT-2012-08-6276
dc.descriptiontext
dc.description.abstractSynucleins represent a conserved family of small proteins that include α-, β-, and γ- isoforms, which are highly expressed in neurons of the vertebrate nervous system. The normal function of these proteins is not well understood. However, in humans α- synuclein dysfunction is causatively linked to Parkinson’s Disease (PD), where it abnormally accumulates in neuronal cell bodies as protein aggregates that are associated with neuronal death. Although the associations between synuclein accumulation and cellular death are established in PD, the extent to which this occurs in other contexts, such as neuronal injury, is unknown. Furthermore, the effects of synuclein aggregation on the function of synapses, where synuclein is normally localized, are not well understood. To address these questions I took advantage of the experimentally accessible nervous system of the sea lamprey (Petromyzon marinus). I used molecular cloning and phylogenetic analyses to characterize three lamprey synuclein orthologues, one of which is highly expressed within a class of neurons called the giant reticulospinal (RS) neurons. Spinal cord injury induces the accumulation of synuclein protein only within a population of poor surviving RS neurons, and this accumulation is correlated with cellular death. Thus, similar to PD, the abundance of synuclein protein is associated with neuronal toxicity. In a related project, I demonstrated that elevating synuclein levels at synapses, such as occurs in PD, is deleterious to synaptic function through an inhibition of synaptic vesicle (SV) recycling. By injecting excess synuclein protein directly into the axons of giant RS neurons, and analyzing the ultrastructural morphology of synapses, I have shown that clathrin-mediated synaptic vesicle endocytosis was greatly inhibited. The conserved N-terminal domain was sufficient to inhibit vesicle recycling, and injecting synuclein mutants with disrupted N-terminal α-helices caused reduced defects in SV recycling. Therefore the α-helical structure of the N-terminus is necessary to inhibit SV recycling at early stages of clathrin-mediated endocytosis. Binding interactions with clathrin-mediated endocytosis components, such as the phosphoinositide lipid PI(4)P support this hypothesis. These studies provide a better understanding of the mechanisms by which synuclein dysfunction leads to neuronal death after injury and synaptic dysfunction in PD and other synuclein-associated diseases.
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.subjectSynuclein
dc.subjectLamprey
dc.subjectSpinal cord injury
dc.subjectReticulospinal neurons
dc.subjectParkinson's Disease
dc.subjectNeurodegeneration
dc.subjectNeuronal death
dc.subjectVesicle recycling
dc.subjectSynapse
dc.subjectClathrin-mediated endocytosis
dc.titleDeleterious effects of synuclein in injury-induced neurodegeneration and in a synaptic model of Parkinson’s Disease
dc.date.updated2012-10-03T21:33:43Z
dc.identifier.slug2152/ETD-UT-2012-08-6276
dc.description.departmentCellular and Molecular Biology
dc.type.genrethesis*
thesis.degree.departmentCellular and Molecular Biology
thesis.degree.disciplineCell and Molecular Biology
thesis.degree.grantorUniversity of Texas at Austin
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy


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