Subcellular compartmentalisation of copper, iron, manganese, and zinc in the Parkinson's disease brain.

Sian Genoud,Adam P Gunn,Kay L Double,Helen J Ball,Simon J G Lewis,Glenda M Halliday,Blaine R Roberts,Dominic J Hare

doi:10.1039/c7mt00244k

Abstract

Elevated iron and decreased copper levels are cardinal features of the degenerating substantia nigra pars compacta in the Parkinson's disease brain. Both of these redox-active metals, and fellow transition metals manganese and zinc, are found at high concentrations within the midbrain and participate in a range of unique biological reactions. We examined the total metal content and cellular compartmentalisation of manganese, iron, copper and zinc in the degenerating substantia nigra, disease-affected but non-degenerating fusiform gyrus, and unaffected occipital cortex in the post mortem Parkinson's disease brain compared with age-matched controls. An expected increase in iron and a decrease in copper concentration was isolated to the soluble cellular fraction, encompassing both interstitial and cytosolic metals and metal-binding proteins, rather than the membrane-associated or insoluble fractions. Manganese and zinc levels did not differ between experimental groups. Altered Fe and Cu levels were unrelated to Braak pathological staging in our cases of late-stage (Braak stage V and VI) disease. The data supports our hypothesis that regional alterations in Fe and Cu, and in proteins that utilise these metals, contribute to the regional selectively of neuronal vulnerability in this disorder.

Highlights

NSW 2007, Australia i Department of Pathology, The University of Melbourne, Parkville, VIC 3052, Australia † Electronic supplementary information (ESI) available
Copper concentrations were regionally varied in the healthy brain with significantly higher levels of Cu in the healthy substantia nigra (SN) compared with the occipital cortex (OCx) and fusiform gyrus (FUS) (+153% vs. OCx, p o 0.01; +233% vs. FUS, p o 0.001; one-way analysis of variance (ANOVA); Fig. 1a)
The concentration of Cu in the Parkinson’s disease SN was approximately half that of control SN (À54%, p o 0.05; Student’s twotailed t-test), resulting in the significant difference between nigral Cu concentration and that in the OCx and FUS observed in the healthy brain being absent in Parkinson’s disease tissue

Summary

Introduction

See DOI: 10.1039/ c7mt00244k structure and enzymatic function.[2] Alterations in the levels and distribution of these transition metals are consistently reported in the Parkinson’s disease brain,[3,4] with the best documented change being elevated levels of Fe in the substantia nigra pars compacta (SNc). Abnormal deposition of Fe in the Parkinson’s disease brain was first reported in 1924;5 since numerous studies have identified significantly increased Fe levels within vulnerable brain regions in this disorder beyond those observed in healthy aged-matched brains.[6,7]. A concomitant decrease in Cu concentration has been reported in degenerating regions of the Parkinson’s disease brain,[8,9] while data regarding Zn levels are conflicting.[3,10] Occupational exposure to Mn alone has been demonstrated to cause parkinsonism,[11] highlighting the necessity for tight Mn regulation in the brain

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