title: Synthesis, Structure Characterization, and Evaluation in Microglia Cultures of Neuromelanin Analogues Suitable for Modeling Parkinson's Disease.
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.
authors.affiliation: Institute of Biomedical Technologies, National Research Council of Italy , Via Fratelli Cervi 93, 20090 Segrate (Milan), Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Ferrari
authors.affiliation: Department of Chemistry, University of Pavia , Via Taramelli 12, 27100 Pavia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Capucciati
authors.affiliation: Institute of Neuroscience, National Research Council of Italy , Via Luigi Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Prada
authors.affiliation: Institute of Biomedical Technologies, National Research Council of Italy , Via Fratelli Cervi 93, 20090 Segrate (Milan), Italy.
authors.forename: Fabio Andrea
authors.initials: FA
authors.lastname: Zucca
authors.affiliation: Institute of Neuroscience, National Research Council of Italy , Via Luigi Vanvitelli, 32, 20129 Milano, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: D'Arrigo
authors.affiliation: Department of Physics and Earth Sciences "M. Melloni", University of Parma , Parco Area delle Scienze 7/A, 43124 Parma, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Pontiroli
authors.affiliation: Department of Physics and Earth Sciences "M. Melloni", University of Parma , Parco Area delle Scienze 7/A, 43124 Parma, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Bridelli
authors.affiliation: Department of Chemistry, University of Pavia , Via Taramelli 12, 27100 Pavia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Sturini
authors.affiliation: Department of Biology, University of Padova , Via Ugo Bassi 58/B, 35131 Padova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bubacco
authors.affiliation: Department of Chemistry, University of Pavia , Via Taramelli 12, 27100 Pavia, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Monzani
authors.affiliation: Institute of Neuroscience, National Research Council of Italy , Via Luigi Vanvitelli, 32, 20129 Milano, Italy.|IRCCS Humanitas , Via Manzoni 56, 20089 Rozzano (Milan), Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Verderio
authors.affiliation: Institute of Biomedical Technologies, National Research Council of Italy , Via Fratelli Cervi 93, 20090 Segrate (Milan), Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Zecca
authors.affiliation: Department of Chemistry, University of Pavia , Via Taramelli 12, 27100 Pavia, Italy.
authors.forename: Luigi
authors.identifier: 0000-0002-7671-0506
authors.initials: L
authors.lastname: Casella
mesh_terms: D000682:Amyloid / Q000493:pharmacokinetics; D000818:Animals; D000831:Animals, Newborn; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D000091344:Filaggrin Proteins; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007782:Lactoglobulins / Q000493:pharmacokinetics; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000378:metabolism; D008543:Melanins / Q000032:analysis* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects* / Q000648:ultrastructure; D008954:Models, Biological; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
chemical_list: D000682:Amyloid; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D053583:Interleukin-1beta; D007782:Lactoglobulins; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008543:Melanins; D011956:Receptors, Cell Surface; C014121:neuromelanin; D007501:Iron; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C574619:ARG1 protein, human; D001119:Arginase; D004298:Dopamine
keywords: Neuromelanin; Parkinson’s disease; amyloid fibrils; iron; microglia; synthetic melanin