Abstract
In the substantia nigra of human brain, neuromelanin (NM) released by degenerating neurons can activate microglia with consequent neurodegeneration, typical of Parkinson's disease (PD). Synthetic analogues of NM were prepared to develop a PD model reproducing the neuropathological conditions of the disease. Soluble melanin-protein conjugates were obtained by melanization of fibrillated β-lactoglobulin (fLG). The melanic portion of the conjugates contains either eumelanic (EufLG) or mixed eumelanic/pheomelanic composition (PheofLG), the latter better simulating natural NMs. In addition, the conjugates can be loaded with controlled amounts of iron. Upon melanization, PheofLG-Fe conjugates maintain the amyloid cross-β protein core as the only structurally organized element, similarly to human NMs. The similarity in composition and structural organization with the natural pigment is reflected by the ability of synthetic NMs to activate microglia, showing potential of the novel conjugates to model NM induced neuroinflammation. Thus, synthetic NM/microglia constitute a new model to develop anti-Parkinson drugs.
Keywords:
Neuromelanin; Parkinson’s disease; amyloid fibrils; iron; microglia; synthetic melanin.
MeSH terms
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Amyloid / pharmacokinetics
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Animals
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Animals, Newborn
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Arginase / genetics
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Arginase / metabolism
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Cells, Cultured
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Dopamine / metabolism
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Filaggrin Proteins
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Humans
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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Iron / metabolism
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Lactoglobulins / pharmacokinetics
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Lectins, C-Type / genetics
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Lectins, C-Type / metabolism
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Mannose Receptor
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Mannose-Binding Lectins / genetics
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Mannose-Binding Lectins / metabolism
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Melanins / analysis*
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Melanins / chemical synthesis*
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Melanins / chemistry
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Melanins / pharmacology*
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Microglia / drug effects*
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Microglia / ultrastructure
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Models, Biological
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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Parkinson Disease / pathology*
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Rats
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Rats, Sprague-Dawley
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Substantia Nigra / drug effects
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Substantia Nigra / metabolism
Substances
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Amyloid
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FLG protein, human
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Filaggrin Proteins
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Interleukin-1beta
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Lactoglobulins
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Lectins, C-Type
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Mannose Receptor
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Mannose-Binding Lectins
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Melanins
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Receptors, Cell Surface
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neuromelanin
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Iron
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Nitric Oxide Synthase Type II
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Cyclooxygenase 2
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Ptgs2 protein, rat
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ARG1 protein, human
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Arginase
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Dopamine