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Abstract
BackgroundNeuromelanin-pigmented neurons, which are highly susceptible to neurodegeneration in the Parkinson’s disease substantia nigra, harbour elevated iron levels in the diseased state. Whilst it is widely believed that neuronal iron is stored in an inert, ferric form, perturbations to normal metal homeostasis could potentially generate more reactive forms of iron capable of stimulating toxicity and cell death. However, non-disruptive analysis of brain metals is inherently challenging, since use of stains or chemical fixatives, for example, can significantly influence metal ion distributions and/or concentrations in tissues. AimsThe aim of this study was to apply synchrotron soft x-ray spectromicroscopy to the characterisation of iron deposits and their local environment within neuromelanin-containing neurons of Parkinson’s disease substantia nigra. MethodsSoft x-ray spectromicroscopy was applied in the form of Scanning Transmission X-ray Microscopy (STXM) to analyse resin-embedded tissue, without requirement for chemically disruptive processing or staining. Measurements were performed at the oxygen and iron K-edges in order to characterise both organic and inorganic components of anatomical tissue using a single label-free method. ResultsSTXM revealed evidence for mixed oxidation states of neuronal iron deposits associated with neuromelanin clusters in Parkinson’s disease substantia nigra. The excellent sensitivity, specificity and spatial resolution of these STXM measurements showed that the iron oxidation state varies across sub-micron length scales. ConclusionsThe label-free STXM approach is highly suited to characterising the distributions of both inorganic and organic components of anatomical tissue, and provides a proof-of-concept for investigating trace metal speciation within Parkinson’s disease neuromelanin-containing neurons.
Highlights
Many neurodegenerative disorders are associated with altered metal ion metabolism in the brain [1]
Despite the association between elevated iron levels and Parkinson’s disease (PD) having been recognised for nearly a century, the mechanisms linking iron dysregulation and neurotoxicity are not yet fully understood, and it remains unclear as to why dopaminergic neurons in the substantia nigra pars compacta (SNc) are so heavily affected by neurodegeneration, whilst other iron-rich nuclei are spared [13]
This work demonstrates that Scanning Transmission X-ray Microscopy (STXM) is a powerful tool for analysing NM clusters and associated iron distributions within neuromelanincontaining neurons, without requirement for chemically disruptive staining
Summary
Many neurodegenerative disorders are associated with altered metal ion metabolism in the brain [1]. In Parkinson’s disease (PD), iron levels are significantly elevated in the type of nerve cell most severely compromised by disease progression – the dopaminergic neurons within the substantia nigra pars compacta (SNc) region [2]. Death of these vulnerable dopamine-producing neurons leads to a severe depletion of striatal dopamine, inducing the characteristic symptoms of PD such as tremor, rigidity and bradykinesia. Conclusions: The label-free STXM approach is highly suited to characterising the distributions of both inorganic and organic components of anatomical tissue, and provides a proof-of-concept for investigating trace metal speciation within Parkinson’s disease neuromelanin-containing neurons
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