Neuronal hemoglobin affects dopaminergic cells’ response to stress

Codrich, Marta; Bertuzzi, Maria; Russo, Roberta; Francescatto, Margherita; Espinoza, Stefano; Zentilin, Lorena; Giacca, Mauro; Cesselli, Daniela; Beltrami, Antonio Paolo; Ascenzi, Paolo; Zucchelli, S.; Persichetti, Francesca; Leanza, Giampiero; Gustincich, Stefano

doi:10.1038/cddis.2016.458

Cited by 27 publications

(42 citation statements)

References 56 publications

(78 reference statements)

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“…One possible explanation could come from some neuronal hemoglobin behavioral effects that were recently shown overexpressing both α- and β-globin chains in mice substantia nigra . Indeed, upon Hb overexpression, mice presented motor skill learning impairments (Codrich et al, 2017 ), suggesting a possible role of Hb in neuronal damage occurring in substantia nigra of PD affected patients. In a similar way, the impaired coordination commonly observed in vCJD cases (Spencer et al, 2002 ), could derive from the aggregation of Hb, probably originating from its transcriptional up-regulated levels.…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin mRNA Changes in the Frontal Cortex of Patients with Neurodegenerative Diseases

et al. 2018

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Background: Hemoglobin is the major protein found in erythrocytes, where it acts as an oxygen carrier molecule. In recent years, its expression has been reported also in neurons and glial cells, although its role in brain tissue remains still unknown. Altered hemoglobin expression has been associated with various neurodegenerative disorders. Here, we investigated hemoglobin mRNA levels in brains of patients affected by variant, iatrogenic, and sporadic forms of Creutzfeldt-Jakob disease (vCJD, iCJD, sCJD, respectively) and in different genetic forms of prion diseases (gPrD) in comparison to Alzheimer's disease (AD) subjects and age-matched controls.Methods: Total RNA was obtained from the frontal cortex of vCJD (n = 20), iCJD (n = 11), sCJD (n = 23), gPrD (n = 30), and AD (n = 14) patients and age-matched controls (n = 30). RT-qPCR was performed for hemoglobin transcripts HBB and HBA1/2 using four reference genes for normalization. In addition, expression analysis of the specific erythrocyte marker ALAS2 was performed in order to account for blood contamination of the tissue samples. Hba1/2 and Hbb protein expression was then investigated with immunofluorescence and confocal microscope analysis.Results: We observed a significant up-regulation of HBA1/2 in vCJD brains together with a significant down-regulation of HBB in iCJD. In addition, while in sporadic and genetic forms of prion disease hemoglobin transcripts did not shown any alterations, both chains display a strong down-regulation in AD brains. These results were confirmed also at a protein level.Conclusions: These data indicate distinct hemoglobin transcriptional responses depending on the specific alterations occurring in different neurodegenerative diseases. In particular, the initial site of misfolding event (central nervous system vs. peripheral tissue)—together with specific molecular and conformational features of the pathological agent of the disease—seem to dictate the peculiar hemoglobin dysregulation found in prion and non-prion neurodegenerative disorders.In addition, these results suggest that gene expression of HBB and HBA1/2 in brain tissue is differentially affected by distinct prion and prion-like aggregating protein strains. Validation of these results in more accessible tissues could prompt the development of novel diagnostic tests for neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 99%

Hemoglobin mRNA Changes in the Frontal Cortex of Patients with Neurodegenerative Diseases

et al. 2018

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“…It was subsequently shown that in A9 neurons, Hb conserves its canonical α2β2 tetrameric structure in vitro and in vivo suggesting that neuronal Hb preserves some of its biochemical activities and biological functions associated to its role in the erythroid lineage [ 117 ]. In the case of Parkinson's disease, it was also shown that Hb forms insoluble aggregates in nucleoli and mitochondria of A9 neurons when overexpressed in vitro and in vivo and upon neurochemical mitochondrial stress [ 118 ]. This phenomenon was accompanied by decreased pre-rRNA transcription, inducing ultimately nucleolar stress and cell damage, as well as a decrease in the H3 methylation status [ 118 ].…”

Section: Hemoglobinmentioning

confidence: 99%

“…In the case of Parkinson's disease, it was also shown that Hb forms insoluble aggregates in nucleoli and mitochondria of A9 neurons when overexpressed in vitro and in vivo and upon neurochemical mitochondrial stress [ 118 ]. This phenomenon was accompanied by decreased pre-rRNA transcription, inducing ultimately nucleolar stress and cell damage, as well as a decrease in the H3 methylation status [ 118 ]. Strikingly, mice overexpressing neuronal Hb displayed aggregates and motor behavior defects after only one month of vector injection.…”

Section: Hemoglobinmentioning

confidence: 99%

“…Strikingly, mice overexpressing neuronal Hb displayed aggregates and motor behavior defects after only one month of vector injection. These observations led the authors to speculate on a function of Hb as energy status sensor of neurons, as well as on additional functions linking Hb to ribosome biogenesis, autophagy and epigenetic regulation [ 118 ]. Similar findings relating Hb to neuronal energetics and epigenetic changes to histones were proposed for multiple sclerosis, further supporting a mitochondrial-associated neuroprotective function of Hb, possibly in an erythropoietin-dependent manner [ 119 , 120 ].…”

Section: Hemoglobinmentioning

confidence: 99%

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Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport

et al. 2020

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Vertebrate hemoglobin (Hb) and myoglobin (Mb) were among the first proteins whose structures and sequences were determined over 50 years ago. In the subsequent pregenomic period, numerous related proteins came to light in plants, invertebrates and bacteria, that shared the myoglobin fold, a signature sequence motif characteristic of a 3-on-3 α-helical sandwich. Concomitantly, eukaryote and bacterial globins with a truncated 2-on-2 α-helical fold were discovered. Genomic information over the last 20 years has dramatically expanded the list of known globins, demonstrating their existence in a limited number of archaeal genomes, a majority of bacterial genomes and an overwhelming majority of eukaryote genomes. In vertebrates, 6 additional globin types were identified, namely neuroglobin (Ngb), cytoglobin (Cygb), globin E (GbE), globin X (GbX), globin Y (GbY) and androglobin (Adgb). Furthermore, functions beyond the familiar oxygen transport and storage have been discovered within the vertebrate globin family, including NO metabolism, peroxidase activity, scavenging of free radicals, and signaling functions. The extension of the knowledge on globin functions suggests that the original roles of bacterial globins must have been enzymatic, involved in defense against NO toxicity, and perhaps also as sensors of O 2 , regulating taxis away or towards high O 2 concentrations. In this review, we aimed to discuss the evolution and remarkable functional diversity of vertebrate globins with particular focus on the variety of non-canonical expression sites of mammalian globins and their according impressive variability of atypical functions.

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“…In hypoxia, Hb appeared to be neuroprotectant by rendering cells into an oxygen privileged state (Schelshorn et al, 2009). However, neurodegenerative effects of Hb expression were also proposed (in aging, Blalock et al, 2003; by promoting Ab oligomerization, Wu et al, 2004; by toxic Hb aggregate formation, Richter et al, 2009; and by learning impairments, Codrich et al, 2017). In hippocampus specifically, chronic stress lead to significant downregulation of Hb genes (Andrus et al, 2012), whereas early-life iron deficiency anemia altered the development and long-term expression of parvalbumin and perineuronal nets (Callahan et al, 2013).…”

Section: Switch Of Transcriptomic States and Rapid Onset Of Hb Expresmentioning

confidence: 99%

Transcriptomic homogeneity and an age-dependent onset of hemoglobin expression characterize morphological PV types

Que

Lukacsovich

Földy

2020

Preprint

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The diversity created by >100 different neural cell types fundamentally contributes to brain function and a central idea is that neuronal identity can be inferred from genetic information.Recent large-scale transcriptomic assays seem to confirm this hypothesis, but a lack of morphological information has limited the identification of several known cell types. For example, parvalbumin interneurons (PV-INs) comprise of a main transcriptomic cluster within all inhibitory cells. However, transcriptomics alone has not resolved the different morphological PV types that exist. To close this gap, we used single-cell RNA-seq in morphologically identified PV-INs, sampled from 10 days to 3 months-old mice and studied their transcriptomic states in the morphological, physiological, and developmental domains. Our findings reveal novel genes whose expression separately identify morphological types but corroborate an overall transcriptomic homogeneity among PV-INs. Surprisingly, morphological PV types display uniform cell adhesion molecule (CAM) profiles, suggesting that CAMs do not actively maintain their specificity of wiring after development. Finally, our results reveal a pronounced change of transcriptomic states between postnatal days 20 and 25, during which PV-INs display a rapid and unexpected onset of hemoglobin gene expression which remains stable in later development.

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Neuronal hemoglobin affects dopaminergic cells’ response to stress

Cited by 27 publications

References 56 publications

Hemoglobin mRNA Changes in the Frontal Cortex of Patients with Neurodegenerative Diseases

Hemoglobin mRNA Changes in the Frontal Cortex of Patients with Neurodegenerative Diseases

Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport

Transcriptomic homogeneity and an age-dependent onset of hemoglobin expression characterize morphological PV types

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