Renton, A.E.M.; (2010) Gene expression and genetic analyses in Parkinson’s disease with and without dementia. Doctoral thesis , UCL (University College London).

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Abstract

Dementia occurs in ~30% of Parkinson’s disease (PD) patients, but few studies have examined gene expression in the brains of these individuals. In this thesis, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and microarray were used to investigate gene expression in the dorsolateral prefrontal cortex (DLPFC), comparing idiopathic Parkinson’s disease (IPD) patients with and without dementia against each other and controls. Expression of the Extracellularsignal regulated kinase 1/2 (ERK1/2) inhibitor Dual specificity phosphatase 6 (DUSP6) and the tyrosine kinase Ephrin receptor A2 (EPHA2) was significantly decreased and increased, respectively, in IPD versus controls, however these phenotypes were unaffected by dementia status. Expression of the PD gene α-Synuclein (SNCA) was unaltered in the DLPFC. Further qRT-PCR analyses demonstrated that DUSP6, EPHA2, and SNCA are not differentially-expressed in seven other regions of the IPD brain. Association and imaging analyses indicated that variation at the DUSP6 single nucleotide polymorphism (SNP) rs1689408 marginally alters IPD risk and profoundly influences grey matter density, possibly through an effect on DUSP6 splicing. Moreover, variation at the EPHA2 SNP rs11260822 significantly modified IPD susceptibility. However, variation at these SNPs did not influence the overall expression of DUSP6 or EPHA2, respectively. In addition, a rare haplotype composed of the SNCA SNPs rs11931074 and rs3822086 significantly increased IPD risk. Detailed examination of the microarray data suggested that pathways involving inflammation, cell adhesion, the cytoskeleton, synaptic transmission, lipoprotein metabolism, metal binding, and mitochondria are dysregulated in the DLPFC of IPD dementia patients. Furthermore, in silico mining of the microarray data suggested that a positive feedback loop involving EPHA2 and ERK1/2 signaling is constitutively-activated in the IPD neurodegeneration DLPFC. Notwithstanding the observed changes, the parkinsonian DLPFC was characterised by an overall lack of gene dysregulation. These findings extend our knowledge of gene expression in IPD dementia and neurodegeneration. Moreover, they suggest that DUSP6 and EPHA2 are novel genes involved in IPD pathogenesis.

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