Whole-Body Lifetime Occupational Lead Exposure and Risk of Parkinson’s Disease

Coon, Steven W.; Stark, Azadeh; Peterson, Edward L.; Gloi, Aime M; Kortsha, Gene X.; Pounds, Joel G.; Chettle, David R.; Gorell, Jay M.

doi:10.1289/ehp.9102

Cited by 159 publications

(109 citation statements)

References 26 publications

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“…30 Lead is a well-known toxic heavy metal that is associated with several neurodegenerative disorders, including PD: Coon et al studied 121 PD patients and showed that occupational lead exposure is a risk factor for PD. 35 Part of the toxic response to Pb(II) exposure is the formation of aggresometype inclusions in target cells, a process which was shown to be controlled by α-syn, among other proteins. 36 Because copper is redox-active in the brain, it has been hypothesized that dysregulation of copper homeostasis, for example, through abnormal binding to α-syn, could catalyze the formation of noxious ROS and thus contribute to neurodegeneration via increased oxidative stress.…”

Section: ' Results and Discussionmentioning

confidence: 99%

Phosphorylation of α-Synuclein at Y125 and S129 Alters Its Metal Binding Properties: Implications for Understanding the Role of α-Synuclein in the Pathogenesis of Parkinson’s Disease and Related Disorders

Prudent

Fauvet

et al. 2011

ACS Chem. Neurosci.

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α-Synuclein (α-syn) is a 140-amino acid protein that plays a central role in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies. However, the molecular determinants that are responsible for triggering and/or propagating α-syn aggregation and toxicity remain poorly understood. Several studies have suggested that there are direct interactions between different metals and α-syn, but the role of metal ions and α-syn in the pathogenesis of PD is not firmly established. Interestingly, the majority of disease-associated post-translational modifications (PTMs) (e.g., truncation, phosphorylation, and nitration) of α-syn occur at residues within the C-terminal region (Y125, S129, Y133, and Y136) and in very close proximity to the putative metal binding sites. Therefore, we hypothesized that phosphorylation within this domain could influence the α-syn–metal interactions. In this paper, we sought to map the interactions between the di- and trivalent cations, Cu(II), Pb(II), Fe(II), and Fe(III), and the C-terminal region of α-syn encompassing residues 107–140 and to determine how phosphorylation at S129 or Y125 alters the specificity and binding affinity of metals using electrospray ionization-mass spectrometry (ESI-MS) and fluorescence spectroscopy. We demonstrate that D115-M116 and P128-S129 act as additional Cu(II) binding sites and show for the first time that the residues P128-S129 and D119 are also involved in Pb(II) and Fe(II) coordination, although D119 is not essential for binding to Fe(II) and Pb(II). Furthermore, we demonstrate that phosphorylation at either Y125 or S129 increases the binding affinity of Cu(II), Pb(II), and Fe(II), but not Fe(III). Additionally, we also show that phosphorylations at these residues lead to a shift in the binding sites of metal ions from the N-terminus to the C-teminus. Together, our findings provide critical insight into and expand our understanding of the molecular and structural bases underlying the interactions between α-syn and metal ions, including the identification of novel metal binding sites, and highlight the potential importance of cross-talk between post-translational modifications and metal ion binding in modulating α-syn functional and aggregation properties that are regulated by its C-terminal domain.

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Section: ' Results and Discussionmentioning

confidence: 99%

Phosphorylation of α-Synuclein at Y125 and S129 Alters Its Metal Binding Properties: Implications for Understanding the Role of α-Synuclein in the Pathogenesis of Parkinson’s Disease and Related Disorders

Prudent

Fauvet

et al. 2011

ACS Chem. Neurosci.

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“…Neuromelanin in the substantia nigra also accumulates an extremely high amount of lead. Such a high influx of lead into dopaminergic neurons could underlie the reported increase of risk for Parkinson's disease in occupational exposure to lead (29). In the past, people were exposed to organic lead by leaded gasoline, and that lead could cross the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 99%

New melanic pigments in the human brain that accumulate in aging and block environmental toxic metals

Zecca

Bellei²,

Costi³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

211

355

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Neuronal pigments of melanic type were identified in the putamen, cortex, cerebellum, and other major regions of human brain. These pigments consist of granules 30 nm in size, contained in organelles together with lipid droplets, and they accumulate in aging, reaching concentrations as high as 1.5-2.6 g/mg tissue in major brain regions. These pigments, which we term neuromelanins, contain melanic, lipid, and peptide components. The melanic component is aromatic in structure, contains a stable free radical, and is synthesized from the precursor molecule cysteinyl-3,4-dihydroxyphenylalanine. This contrasts with neuromelanin of the substantia nigra, where the melanic precursor is cysteinyl-dopamine. These neuronal pigments have some structural similarities to the melanin found in skin. The precursors of lipid components of the neuromelanins are the polyunsaturated lipids present in the surrounding organelles. The synthesis of neuromelanins in the various regions of the human brain is an important protective process because the melanic component is generated through the removal of reactive/toxic quinones that would otherwise cause neurotoxicity. Furthermore, the resulting melanic component serves an additional protective role through its ability to chelate and accumulate metals, including environmentally toxic metals such as mercury and lead.lipids ͉ neuromelanin ͉ brain aging ͉ neurodegenerative

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“…The combination of exposure to lead and iron showed no increased risk compared to exposure to lead alone [322]. Using the same subjects, these authors assessed whole body lifetime lead exposure by measurements of bone lead stores in combination with occupational history and reported an increased risk of PD for the 4 th quartile of whole body lifetime lead exposure compared to the 1 st quartile (OR 2.27, 95% CI 1.13-4.55) [383].…”

Section: Metalsmentioning

confidence: 98%