UCLA

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder characterized by a loss of nigrostriatal dopaminergic neurons. Although the etiology of PD is largely unknown, it is thought to arise from a combination of genetic and environmental factors. Alpha-synuclein, a protein involved in familial PD and a major constituent of the Lewy bodies found in sporadic PD, has recently been implicated as an initiator of microglial activation and neuroinflammatory processes in the pathogenesis of PD. The objective of this study was to determine if alpha-synuclein overexpression in the absence of overt neurodegeneration is sufficient to trigger microglial activation and the timeline of these inflammatory events. To test this hypothesis, I used the Thy1-aSyn mouse model, which overexpresses human wildtype alpha-synuclein under the Thy-1 promoter. These mice demonstrate early and progressive sensorimotor anomalies in behavioral tests sensitive to nigrostriatal dysfunction and olfactory deficits, showing a loss of dopamine at 14 months of age. Previous studies by our group revealed that there was phenotypically specific microglial activation in the substantia nigra and striatum of Thy1-aSyn mice at 6 and 14 months of age, which was associated with exclusively increased TNF-α levels. This present thesis specifically examined neuroinflammation in Thy1-aSyn mice at 1 month of age to determine whether similar patterns of microglial activation are evident in earlier stages of development. By using Iba-1 immunohistochemistry, I found that there was a significant increase in microglial activation exclusively in the striatum of Thy1-aSyn mice compared to wildtype at 1 month of age. Microglial activation was accompanied by increased striatal TNF-α mRNA expression measured by quantitative RT-PCR. Tyrosine hydroxylase (TH) immunofluorescence confirmed that such changes in neuroinflammation occurred in the absence of dopaminergic terminal loss in the nigrostriatal pathway, and synaptophysin immunofluorescence evaluated the absence of synaptic loss in the striatum. Together, these data demonstrate that widespread overexpression of alpha-synuclein results in early microglial activation in the striatum that is associated with a distinct pro-inflammatory cytokine increase characterized by TNF-α production. Thus, the results of this study suggest that alpha-synuclein overexpression itself is capable of activating early inflammatory events that may be associated with PD pathology.