Dopaminergic neurons (DA) are an anatomically and functionally heterogeneous group of cells involved in a wide range of neuronal network activities and behaviour. Among them, mesencephalic dopaminergic neurons (mDA) are the major source of dopamine in the brain. They present two main groups of projecting cells: the A9 neurons of the Substantia Nigra (SN) and the A10 cells of the Ventral Tegmental Area (VTA). A9 neurons form the nigrostriatal pathway and are involved in regulating voluntary movements and postural reflexes. Their selective degeneration leads to Parkinson’s disease (PD) and the loss of DA synapses in the striatum is believed to be primary cause for the disruption of the ability to control movements (E. Hirsch et al. 1988). A10 cells constitute the mesocorticolimbic pathway playing a fundamental role in reward and attention. Their abnormal function has been linked to schizophrenia, attention deficit and addiction while they are relatively spared in PD (Meyer-Lindenberg et al. 2002). The description of the repertory of genes of mDA neurons may provide crucial information on their physiology as well as on the mechanisms of cell-type specific dysfunction. Interestingly, in previous gene expression profiling experiments, mDA cells groups presented a limited number of differentially expressed genes with A9-enriched transcripts mainly related to energy metabolism and mitochondrial function (C. Y. Chung et al. 2005; James G Greene et al. 2005). A crucial requirement for metabolically active aerobic cells is a steady supply of oxygen. To this purpose, hemoglobin-like molecules occur widely in organisms ranging form bacteria to human (Vandergon 1998). Vertebrate hemoglobin is the oxygen- and carbon dioxide-carrying protein in cells of erythroid lineage and is responsible for oxygen delivery to the respiring tissues of the body. Additional vertebrate heme-containing proteins with structural homology to globin chains include cytoglobin, mostly described in connective tissues (M. Schmidt et al. 2004), and neuroglobin, broadly expressed in the brain (Burmester 2000; Burmester 2004). Surprisingly, hemoglobin chains have been recently detected in non-erythroid cells including macrophages, alveolar cells, eye’s lens and mesangial cells of the kidney (Dugas et al. 2006; L. Liu et al. 1999; Newton et al. 2006; Nishi et al. 2008). By a combination of different gene expression platforms with Laser Capture Microdissection (LCM), we have identified the transcripts of hemoglobin alpha, adult chain 1 (Hba-a1) and hemoglobin beta, adult chain 1 (Hbb-b1) in A9 neurons. Interestingly, Hemoglobin-ImmunoReactivity (Hb-IR) decorated the large majority of A9 cells while stained only less than 5% of A10 neurons. Furthermore, we detected hemoglobin expression in almost all oligodendrocytes as well as in cortical and hippocampal astrocytes and proved that this pattern of expression was conserved in mammals. Importantly, A9 DA neurons from human post mortem brain showed hemoglobin expression. By gene expression analysis of mouse dopaminergic neuroblastoma cell lines stably transfected with alpha- and beta-chains, we observed changes in genes involved in oxygen homeostasis as well as in oxidative phosphorylation, suggesting a link between hemoglobin and mitochondrial activity. These results open a new scenario for hemoglobin role in brain physiology and in PD pathogenesis.
An old protein in unexpected places: alpha- and beta- globin expression in mesencephalic dopaminergic neurons and glial cells [Tesi di dottorato]
Tesi di dottorato. | Lingua: en. | Paese: | BID: TD15088543
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