Neurogenesis regulation in Parkinson's disease

Neurogenesis in Parkinsons disease (PD) is reported to be decreased in the subventricular zone and hippocampus, however neural stem cells removed from these regions were able to be cultured in vitro suggesting that the neurogenic niche of these regions may be altered in the PD brain. Trophic factors have been proposedto be involved in the proliferation and survival of neural stem cells. This thesis aimed to investigate whether trophic factors are changed in the subventricular zone and hippocampus of the PD brain and their localisation. Using enzyme-linked immunoassays, protein levels of epidermal growth factor, glial-derived neurotrophic factor and basic fibroblast growth factor were altered in the PD subventricular zone whilst protein levels of glial-derived neurotrophic factor, basic fibroblast growth factor and cerebral dopamine neurotrophic factor were altered in the PD hippocampus. Immunohistochemistry showed localisation of glial-derived neurotrophic factor and cerebral dopamine neurotrophic factor to neuronal cells in the hippocampus and basic fibroblast growth factor to astrocytes, microglia and neurons. Western blotting did not detect changes in the cellular composition of thehippocampus, however immunohistochemistry demonstrated increased numbers of basic fibroblast growth factor-immunopositive cells with microglial-like morphology in the PD hippocampus. This is the first study investigating trophic changes in these neurogenic regions and these findings suggest that the neurogenic niche in theseregions of the PD brain are altered. Levels of proliferating and immature neuronal cells were investigated in thehippocampus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice to characterise potential neurogenesis changes in this common animal model of PD. Neurogenesis levels in the hippocampus of MPTP-lesioned mice were unchanged suggesting that this model does not reflect neurogenesis changes seen inPD. This work characterises changes in levels of neurotrophic factors in neurogenic regions of the PD brain and investigates levels of cellular proliferation in the MPTP model of this disorder. This thesis increases our understanding of changes occurring in the PD brain and may support the development of stem cell based restorative therapies