Yang, Y.X.; (2007) Characterisation of Parkinson's disease-associated genes and their regulation. Doctoral thesis , University of London.

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Abstract

Parkinson's disease is a highly prevalent neurodegenerative disorder. Several genes have been shown to be associated with familial Parkinson's disease and they usually lead to Parkinson's disease due to the presence of mutations that affect protein function. It has been suggested that variations in the expression of the wild type genes may also lead to Parkinson's disease. The causes of idiopathic Parkinson's disease remain unknown. Several factors may contribute to its onset, including: susceptibility genes, environmental stress and aging. This study aimed to characterize the influence of oxidative stresses on the regulation of genes associated with Parkinson's disease. The effects of oxidative stress on a- synuclein, parkin and PINK1 were investigated in a cell culture model. Both ot- synuclein and parkin were similarly up-regulated when cells were exposed to stresses such as dopamine and l-methyl-4-phenylpyridinium (MPP+). In constrast, PINK1 levels were up-regulated only by MPP+, and were down-regulated in both dopamine and MG132 treatments. This work confirmed and extended previous reports that oxidative stresses are implicated in Parkinson's disease, and also revealed the complexity of the regulation by these stresses. A further study into the regulation of a-synuclein showed a novel interaction between the a-synuclein promoter and an Early Growth Response transcription factor family member in oxidative stress conditions. Moreover, this work demonstrated that several other neuronally expressed transcription factors influenced the regulation of a- synuclein, such as the product of the Parkinson's disease associated gene, Nurrl. The decreased expression of this gene increased a-synuclein transcription. This is of interest, as variations in the levels of either of these genes can cause Parkinson's disease and such an interaction was novel. This work further demonstrated that the POU family trancription factor, Brn3a, was involved in this pathway. Brn3a appeared to function antagonistically to Nurrl in a-synuclein regulation. In addition to studies of gene regulation, mutational and/or protein analysis were performed on Nurrl and PINK1. Studies of PINK 1 protein established the functional importance of cleavage of precursor PINK1 and also provided a better estimation of the location of the cleavage site. These genes are more recent discoveries compared to a-synuclein and parkin, thus, such studies will give important insights into their Parkinson's disease properties.

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