Copper distribution in the normal human brain

Bonilla, Ernesto; Salazar, Enrique Gonzalo Rojas; Villasmil, J.; Villalobos, Rafael; Gónzalez, M.D.; Dávila, José Omar

doi:10.1007/bf00964589

Cited by 26 publications

(12 citation statements)

References 10 publications

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“…However, the K d may be assumed to be well below the micromolar range, consistent with the previously reported value of 0.2 n M at pH 7.4, based on ITC measurements 28. Such an affinity would be consistent with a physiological relevance of the effect of Cu 2+ reported here, because the estimated Cu 2+ concentration in the brain is in the 15–80 μ M range 58–60…”

Section: Discussionsupporting

confidence: 90%

Compact conformations of α‐synuclein induced by alcohols and copper

Natalello¹,

Benetti²,

Doglia³

et al. 2010

Proteins

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The intrinsically disordered protein α-synuclein aggregates into amyloid fibrils, a process known to be implicated in several neurodegenerative states. Partially folded forms of the protein are thought to trigger the aggregation process. Here, α-synuclein conformers are characterized by analysis of the charge-state distributions observed in electrospray-ionization mass spectrometry under negative-ion mode. It is found that, even at neutral pH, a small fraction of the molecular population is in a compact conformation. Several distinct partially folded forms are then identified under conditions that promote α-synuclein aggregation, such as solutions of simple and fluorinated alcohols. Specific intermediates accumulate at increasing concentrations of ethanol, hexafluoro-2-propanol, and trifluoroethanol. Finally, extensive folding induced by Cu(2+) binding is revealed by titrations in the presence of Cu(2+)-glycine. The data confirm the existence of a single, high-affinity binding site for Cu(2+). Because accumulation of this partially folded form correlates with enhancement of fibrillation kinetics, it is likely to represent an amyloidogenic intermediate in α-synuclein conformational transitions.

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Section: Discussionsupporting

confidence: 90%

Compact conformations of α‐synuclein induced by alcohols and copper

Natalello¹,

Benetti²,

Doglia³

et al. 2010

Proteins

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“…3). This pattern was similar to that described for Cu in the human insular cortex (Dobrowolska et al 2008) and in agreement with previous reports indicating that Cu was more abundant in GM than WM in nonhuman primate brain (Bonilla et al 1984; Ramos et al 2014; Knauer et al 2017). Iron was observed in blood vessels, as expected due to its well-known association with hemoglobin, but also along layer IV and infragranular layers.…”

Section: Discussionsupporting

confidence: 92%

Molecular composition of the human primary visual cortex profiled by multimodal mass spectrometry imaging

et al. 2018

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The primary visual cortex (area V1) is an extensively studied part of the cerebral cortex with well-characterized connectivity, cellular and molecular architecture and functions (for recent reviews see Amunts and Zilles, Neuron 88:1086–1107, 2015; Casagrande and Xu, Parallel visual pathways: a comparative perspective. The visual neurosciences, MIT Press, Cambridge, pp 494–506, 2004). In humans, V1 is defined by heavily myelinated fibers arriving from the radiatio optica that form the Gennari stripe in cortical layer IV, which is further subdivided into laminae IVa, IVb, IVcα and IVcβ. Due to this unique laminar pattern, V1 represents an excellent region to test whether multimodal mass spectrometric imaging could reveal novel biomolecular markers for a functionally relevant parcellation of the human cerebral cortex. Here we analyzed histological sections of three post-mortem brains with matrix-assisted laser desorption/ionization mass spectrometry imaging and laser ablation inductively coupled plasma mass spectrometry imaging to investigate the distribution of lipids, proteins and metals in human V1. We identified 71 peptides of 13 different proteins by in situ tandem mass spectrometry, of which 5 proteins show a differential laminar distribution pattern revealing the border between V1 and V2. High-accuracy mass measurements identified 123 lipid species, including glycerolipids, glycerophospholipids and sphingolipids, of which at least 20 showed differential distribution within V1 and V2. Specific lipids labeled not only myelinated layer IVb, but also IVa and especially IVc in a layer-specific manner, but also and clearly separated V1 from V2. Elemental imaging further showed a specific accumulation of copper in layer IV. In conclusion, multimodal mass spectrometry imaging identified novel biomolecular and elemental markers with specific laminar and inter-areal differences. We conclude that mass spectrometry imaging provides a promising new approach toward multimodal, molecule-based cortical parcellation.Electronic supplementary materialThe online version of this article (10.1007/s00429-018-1660-y) contains supplementary material, which is available to authorized users.

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“…The reason for such specific localization of neuronal damage in WND is not yet fully understood. It is anticipated that vulnerability of neurons to copper overload may be region dependent because substantia nigra, tail of caudate nucleus and putamen are the brain structures characterized by the highest copper and iron concentration in humans [9, 15, 16]. The local distribution of copper and iron in brains of toxic milk mice is similar to that in humans [7, 17].…”

Section: Discussionmentioning

confidence: 99%

Neurochemical and Behavioral Characteristics of Toxic Milk Mice: An Animal Model of Wilson’s Disease

et al. 2013

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Toxic milk mice have an inherited defect of copper metabolism. Hepatic phenotype of the toxic milk mice is similar to clinical findings in humans suffering from Wilson’s disease (WND). In the present study, neurotransmitter system and locomotor performance in toxic milk mice was examined to verify the feasibility of this animal model for studying neuropathology of WND. Mice aged 2 and 12 months were used in the experiment. The mice were tested according to rotarod and footprint protocols. Monoamine content in brain structures was measured by high performance liquid chromatography. In order to detect neuronal loss, expression of enzymes specific for dopaminergic [tyrosine hydroxylase (TH)], noradrenergic (dopamine beta-hydroxylase) and serotoninergic [tryptophan hydroxylase (TPH)] neurons was analyzed by Western blot. The 12-month-old toxic milk mice demonstrated impaired locomotor performance in behavioral tests. Motor deficits were accompanied by increased copper and serotonin content in different brain regions and slight decrease in dopamine concentration in the striatum. The expression of TH, dopamine beta-hydroxylase and TPH in the various brain structures did not differ between toxic milk mice and control animals. Despite differences in brain pathology between humans and rodents, further exploration of neuronal injury in toxic milk mice is warranted to broaden the understanding of neuropathology in WND.

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Copper distribution in the normal human brain

Cited by 26 publications

References 10 publications

Compact conformations of α‐synuclein induced by alcohols and copper

Compact conformations of α‐synuclein induced by alcohols and copper

Molecular composition of the human primary visual cortex profiled by multimodal mass spectrometry imaging

Neurochemical and Behavioral Characteristics of Toxic Milk Mice: An Animal Model of Wilson’s Disease

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