Regular articleCopper pathology in vulnerable brain regions in Parkinson's disease
Introduction
Neurodegenerative cascades in Parkinson's disease (PD) involve protein aggregation and oxidative stress, although the triggers for these events are unknown. Changes in biometals have long been suspected to play a role in these cascades. Copper (Cu) is an important biometal in the brain, as exemplified by Menkes and Wilson diseases, serious neurological disorders of Cu dyshomeostasis (Schaefer and Gitlin, 1999, de Bie et al., 2007). A significant decrease in total tissue Cu in the degenerating substantia nigra (SN) in PD has been consistently reported over a number of decades (Ayton et al., 2012, Dexter et al., 1989, Loeffler et al., 1996, Popescu et al., 2009, Uitti et al., 1989), and recent evidence suggests that peripheral Cu metabolism is altered in PD (Larner et al., 2013). The complexing of Cu with the PD-associated protein α-synuclein increases aggregation and toxicity of this protein (Rose et al., 2011, Wang et al., 2010), possibly via stimulation of free radical production (Meloni and Vasak, 2011). However, Cu is also a critical cofactor in a range of cuproproteins, including the key protective cellular antioxidant superoxide dismutase 1 (SOD1) (McCord and Fridovich, 1969). Studies in model systems demonstrate that Cu depletion is associated with reduced activity of SOD1 and a concomitant increase in free radical production, which can be normalized by Cu supplementation (Lombardo et al., 2003, Prohaska, 1983). SOD1 activity is reduced in the plasma of PD patients (Torsdottir et al., 2006), and studies in animal models of PD suggest that overexpression of SOD1 increases neuronal survival (Battaglia et al., 2002, Botella et al., 2008, Tripanichkul et al., 2007). These data suggest that a reduction in brain Cu in PD may reduce SOD1-mediated antioxidant defense and contribute to neurodegenerative cascades. In this work, we investigated changes in neuronal Cu levels and transport pathways to determine whether changes in Cu are associated with a reduced antioxidant capacity in regions of neurodegeneration in PD.
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Brain tissue samples
Brain tissue samples were requested and received from the New South Wales Tissue Resource Centre at the University of Sydney and the Sydney Brain Bank at Neuroscience Research Australia. The brain tissue samples were from patients with idiopathic PD and incidental Lewy body disease (ILBD), identified according to the diagnostic criteria of Dickson et al. (2009), and from Alzheimer's disease (AD) and age-matched control subjects, identified according to the diagnostic criteria of Montine et al. (
Decreased Cu precedes regional cell loss in PD
Quantitative analysis of fixed sections by SRXFM (Fig. 1A–1C) revealed a decrease in NM-associated Cu in the SN from PD and ILBD cases with respect to both age-matched control subjects (45% decrease in PD, p < 0.0001% and 48% decrease in ILBD, p = 0.0003) and AD cases (31% decrease in PD, p = 0.003% and 34.5% decrease in ILBD, p = 0.007; Fig. 1A). Our finding of decreased NM-associated Cu levels in the PD SN was confirmed in fresh frozen tissue sections (65%, p < 0.0001; Fig. 2). A
Discussion
The current data demonstrate that Cu and the expression of the Cu transport protein Ctr1 are decreased within the intraneuronal environment of surviving dopaminergic neurons of the SN and LC in ILBD and PD compared with control SN and LC (Fig. 1, Fig. 2, Fig. 3, Fig. 4). Because ILBD is suggested to represent preclinical PD (Dickson et al., 2009) and these cases had not taken anti-parkinsonian medications, this suggests these changes occur early in the disease process and are independent of
Disclosure statement
The authors have no actual or potential conflicts of interest.
Acknowledgements
Tissues were received from the New South Wales Tissue Resource Centre at the University of Sydney, supported by the National Health and Medical Research Council of Australia, Schizophrenia Research Institute, and the National Institute of Alcohol Abuse and Alcoholism (National Institutes of Health grant R24AA012725), and from the Sydney Brain Bank, which is supported by Neuroscience Research Australia, the University of New South Wales and the National Health and Medical Research Council of
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2022, Journal of Inorganic BiochemistryCitation Excerpt :For instance, the partially α-helical structure in the membrane-bound state [2], is essentially important for both the physiological functions and pathological roles of α-Syn [44]. Metal ions like Cu2+ act as a crucial player both for the properties of lipid membranes and the states and functions of α-Syn, as well as in the normal activities of various enzymes [8], with decreased levels in the brains (SN) of PD patients [25]. Therefore, investigating how Cu2+ ions modulate the intercommunication between α-Syn and lipid membranes will provide us with further insights into the molecular pathogenesis.
K.M.D. and S.B. contributed equally to this work.