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Title: Adult generation of dopaminergic neurons in a genetic model of Parkinson's disease
Author: Brown, Sarah
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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In the central nervous system, neuronal population size is a function of the number of neurons generated and the number lost through apoptosis or degeneration. Postnatal neurogenesis has been observed in several areas of the vertebrate brain and a reduced generation of neurons through life could contribute to neurodegenerative disease. Parkinson's disease (PD) is underlain by a reduced number of dopaminergic (DA) neurons, in particular, ascending neurons of the substantia nigra pars compacta. The degeneration of DA neurons is a known contributory factor, but may not account fully for disease pathogenesis. Here I examine the character and generation of DA neurons in the adult zebrafish posterior tuberculum (PT) in wild type and in a model of genetic PD, the pink1 knockout zebrafish. I first characterise embryonic and adult DA neuronal populations in the zebrafish PT and show that throughout life, DA neuronal populations reside close to populations of stem and progenitor cells that are themselves maintained in the PT in adulthood. I show that ascending DA neurons of the PT, functionally-equivalent to those of the substantia nigra, express the transcription factor, OTPb, and that local-projecting DA neurons of the paraventricular organ (PVO) in the ventral PT/dorsal hypothalamus express rx3. Using EdU analyses and lineage-tracing studies, I demonstrate that a subset of ascending DA neurons (those of the periventricular nucleus of the posterior tuberculum (TPp) and the localprojecting DA neurons of the paraventricular organ (PVO)) are generated in adulthood in wild type animals at a rate that decreases with age. Using a robust model of PD, the pink1-/- zebrafish, I show that Pink1-deficiency impedes DA neurogenesis in early adult life. Analysis of population size shows that zebrafish lacking functional Pink1 fail to expand DA neuronal populations in adulthood and display reduced numbers of OTPb-expressing progenitors. Together this work reveals that subsets of ascending DA neurons of the PT and localprojecting DA neurons of PVO in the ventral PT/dorsal hypothalamus are generated throughout life, demonstrates a novel role for Pink1 in adult DA neurogenesis and suggests potential future applications of stimulation of de novo neurogenesis in PD.
Supervisor: Placzek, Marysia ; Bandmann, Oliver Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available