title: Neuronal hemoglobin affects dopaminergic cells' response to stress.
abstract: Hemoglobin (Hb) is the major protein in erythrocytes and carries oxygen (O2) throughout the body. Recently, Hb has been found synthesized in atypical sites, including the brain. Hb is highly expressed in A9 dopaminergic (DA) neurons of the substantia nigra (SN), whose selective degeneration leads to Parkinson's disease (PD). Here we show that Hb confers DA cells' susceptibility to 1-methyl-4-phenylpyridinium (MPP+) and rotenone, neurochemical cellular models of PD. The toxic property of Hb does not depend on O2binding and is associated with insoluble aggregate formation in the nucleolus. Neurochemical stress induces epigenetic modifications, nucleolar alterations and autophagy inhibition that depend on Hb expression. When adeno-associated viruses carrying α- and β-chains of Hb are stereotaxically injected into mouse SN, Hb forms aggregates and causes motor learning impairment. These results position Hb as a potential player in DA cells' homeostasis and dysfunction in PD.
authors.affiliation: Area of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), via Bonomea 265, Trieste 34136, Italy.|Department of Health Sciences, University of Eastern Piedmont 'A. Avogadro', via Solaroli 17, 28100 Novara, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Codrich
authors.affiliation: Area of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), via Bonomea 265, Trieste 34136, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Bertuzzi
authors.affiliation: Area of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), via Bonomea 265, Trieste 34136, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Russo
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), via Morego 30, Genova 16163, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Francescatto
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), via Morego 30, Genova 16163, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Espinoza
authors.affiliation: ICGEB, Padriciano 99, 34149 Trieste, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Zentilin
authors.affiliation: ICGEB, Padriciano 99, 34149 Trieste, Italy.
authors.forename: Mauro
authors.identifier: 0000-0003-2927-7225
authors.initials: M
authors.lastname: Giacca
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, Udine, 33100, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cesselli
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, Udine, 33100, Italy.
authors.forename: Antonio Paolo
authors.identifier: 0000-0002-0679-2710
authors.initials: AP
authors.lastname: Beltrami
authors.affiliation: Department of Sciences, University of Roma Tre, viale G. Marconi 446, Roma 00146, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ascenzi
authors.affiliation: Area of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), via Bonomea 265, Trieste 34136, Italy.|Department of Health Sciences, University of Eastern Piedmont 'A. Avogadro', via Solaroli 17, 28100 Novara, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zucchelli
authors.affiliation: Department of Health Sciences, University of Eastern Piedmont 'A. Avogadro', via Solaroli 17, 28100 Novara, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Persichetti
authors.affiliation: Department of Life Sciences, University of Trieste, via Fleming 22, Trieste 34127, Italy.
authors.forename: Giampiero
authors.initials: G
authors.lastname: Leanza
authors.affiliation: Area of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), via Bonomea 265, Trieste 34136, Italy.|Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), via Morego 30, Genova 16163, Italy.
authors.forename: Stefano
authors.identifier: 0000-0002-2749-2514
authors.initials: S
authors.lastname: Gustincich
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D001343:Autophagy / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D044127:Epigenesis, Genetic / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006454:Hemoglobins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000235:genetics* / Q000473:pathology; D012402:Rotenone / Q000633:toxicity; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology
chemical_list: D006454:Hemoglobins; D012402:Rotenone; D015655:1-Methyl-4-phenylpyridinium