The role of copper in Parkinson's disease

Decreased copper levels has been consistently reported in the degenerating substantia nigra in Parkinsons disease, but the cause, and functional consequences, of this decrease are unknown. This thesis aimed to investigate neuronal copper levels and potential changes in copper transport in the Parkinsons disease brain to determine if altered copper levels associate with altered copper transport and affect the function of the antioxidant cuproprotein, superoxide dismutase 1 (SOD1). Characterisation of regional copper levels, and copper transport pathways in the normal human brain using inductively coupled plasma-mass spectrometry (ICP-MS), western blot and immunohistochemistry demonstrated the substantia nigra contains twice as much copper compared with other brain regions, suggesting an important role for copper in this region. Synchrotron-based X-ray fluorescence microscopy, immunofluorescence, and western blot demonstrated that levels of copper, and copper transporter protein 1, are significantly reduced in the vulnerable substantia nigra and locus coeruleus in Parkinsons disease. The specific activity of SOD1 was upregulated in the non-degenerating anterior cingulate cortex in Parkinsons disease but not in the vulnerable substantia nigra where copper levels are decreased. These findings suggest that a deficit in cellular copper in the substantia nigra prevents a compensatory increase in SOD1 activity in this vulnerable brain region. ICP-MS, high-performance liquid chromatography, western blot and SOD1 assay were used to investigate a novel model, the MPTP-lesioned Mo-br mouse. These animals exhibited both the decreased copper and tissue dopamine in the nigrostriatal pathway characteristic of the human parkinsonian brain. Further, brain SOD1 activity in these animals was significantly associated with tissue copper levels. The copper-modulating ionophore clioquinol effectively increased substantia nigra copper in these animals, suggesting the MPTP-lesioned Mo-br mouse may be a useful model to investigate the potential of brain copper modulation for cell vulnerability. This work characterises copper transport pathways in the healthy human brain and identifies a cellular deficit in copper in vulnerable neurons in Parkinsons disease associated with a functional change in the protective enzyme SOD1. It also characterises a novel mouse model exhibiting similar changes in brain copper and SOD1 activity in which novel therapeutics could be trialled