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Copper, iron and SOD1 in Parkinson’s disease aetiology

Sian Genoud

Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia

Alterations in the essential biometals copper and iron are increasingly implicated in cell death mechanisms of multiple neurodegenerative diseases including Parkinson’s disease (PD). In human post-mortem PD brain tissue, we identified a marked reduction in copper, and significant elevation in iron restricted to the degenerating substantia nigra. This was further restricted to the soluble fraction of tissue, where many metal-dependent proteins reside. We confirm that these copper and iron changes are restricted to the site of neurodegeneration and are consistent among studies employing different PD cohorts and methodological designs, in a meta-analysis of studies reporting quantitative copper and iron levels in human PD substantia nigra, sera and cerebrospinal fluids. In investigating copper-dependent proteins that may be affected by severe copper deficiency in the PD substantia nigra, we have also identified alterations in superoxide dismutase 1 (SOD1) in this region. SOD1 is normally an antioxidant protein that binds copper and zinc in a 1:1 ratio for enzymatic function and structural integrity. In the PD substantia nigra SOD1 activity is reduced and it forms insoluble aggregations. Using synchrotron x-ray fluorescence microscopy, we have identified that these SOD1 aggregates are copper-deficient, which we postulate causes its dysfunction in the PD brain. We postulate that these copper and iron changes are involved in cell death in this disorder. This highlights the need for functional imaging markers of copper and iron to identify these changes in live patients, prior to clinical manifestation of the disorder. These data support the use of biometal modulation such as copper supplementation and iron chelation therapies currently in clinical trial for PD, in an attempt to provide the first disease modifying therapeutic approach for this disorder.