Elsevier

Neurobiology of Aging

Volume 35, Issue 4, April 2014, Pages 858-866
Neurobiology of Aging

Regular article
Copper pathology in vulnerable brain regions in Parkinson's disease

https://doi.org/10.1016/j.neurobiolaging.2013.09.034Get rights and content

Abstract

Synchrotron-based x-ray fluorescence microscopy, immunofluorescence, and Western blotting were used to investigate changes in copper (Cu) and Cu-associated pathways in the vulnerable substantia nigra (SN) and locus coeruleus (LC) and in nondegenerating brain regions in cases of Parkinson's disease (PD) and appropriate healthy and disease controls. In PD and incidental Lewy body disease, levels of Cu and Cu transporter protein 1, were significantly reduced in surviving neurons in the SN and LC. Specific activity of the cuproprotein superoxide dismutase 1 was unchanged in the SN in PD but was enhanced in the parkinsonian anterior cingulate cortex, a region with α-synuclein pathology, normal Cu, and limited cell loss. These data suggest that regions affected by α-synuclein pathology may display enhanced vulnerability and cell loss if Cu-dependent protective mechanisms are compromised. Additional investigation of copper pathology in PD may identify novel targets for the development of protective therapies for this disorder.

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.

Section snippets

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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    K.M.D. and S.B. contributed equally to this work.

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