Disease relevance of Ngb

• Neuroglobin (Ngb), a protein related to myoglobin and hemoglobin but expressed predominantly in the brain, is induced by neuronal hypoxia and cerebral ischemia and protects against hypoxic or ischemic neuronal injury [1].
• In Ngb-overexpressing transgenic mice compared with wild-type littermates, the volume of cerebral infarcts after occlusion of the middle cerebral artery was reduced by approximately 30%, and the volume of myocardial infarcts produced by occlusion of the left anterior descending coronary artery was reduced by approximately 25% [1].
• Neuroglobin-overexpressing transgenic mice are resistant to cerebral and myocardial ischemia [1].
• Neuroglobin is localised in photoreceptor inner segments, the plexiform layers and the ganglion cell layer [2].
• In immunostained mouse brain sections, we found widespread expression of Ngb protein in neurons, but not astrocytes, of several brain regions that are prominently involved in age-related neurodegenerative disorders [3].

High impact information on Ngb

• These findings extend prior evidence for cytoprotection by Ngb and suggest both direct (parenchymatous) and indirect (vasomotor) protective mechanisms [1].
• Ngb overexpression was associated with enhanced expression of endothelial nitric oxide synthase in vascular endothelial cells [1].
• Steady-state amperometric experiments show that Ngb is devoid of O2 reductase and NO reductase activities [4].
• Here, we present the x-ray structure of CO-bound ferrous murine Ngb at 1.7 A and a comparison with the 1.5-A structure of ferric bis-histidine Ngb [5].
• We have also used Fourier transform IR spectroscopy of WT and mutant CO-ligated Ngb to examine structural heterogeneity in the active site [5].

Biological context of Ngb

• While neuroglobin seems to be associated with oxygen consumption, a respiratory function of cytoglobin is unlikely [2].
• The discovery of Ngb in astrocytes may provide some insight into how oxygen homeostasis is regulated in the brain [6].
• Ngb antisense treatment increased apoptosis in ischemic astrocytes [6].
• However, contradicting reports exist regarding localization and up-regulation of Ngb in response to hypoxia [7].

Anatomical context of Ngb

• Western blots from young adult (3 month), middle-aged (12 month), and aged (24 month) rats showed an age-related decline in Ngb expression in cerebral neocortex, hippocampus, caudate-putamen, and cerebellum [3].
• Most, but not all, nerve cells were labeled, suggesting differential expression of Ngb [8].
• Two-hour hypoxic exposure caused no detectable changes in staining intensity or spatial distribution of Ngb neither in the Purkinje cells nor in any other brain areas observed [7].
• We found Ngb to be present throughout the neocortex, most abundantly in the perirhinal, entorhinal and temporal cortical areas, the thalamus and hypothalamus, the choroid plexus, the olfactory bulb and the cranial nerve nuclei in the brainstem [7].
• The distribution of neuroglobin correlates with the subcellular localization of mitochondria and with the relative oxygen demands, as the plexiform layers and the inner segment consume most of the retinal oxygen [9].

Associations of Ngb with chemical compounds

• Ngb is hexacoordinate in the ferrous deoxy form under physiological conditions [10].
• Unlike in Mb, in Ngb the sixth coordination position of the heme iron is occupied by the distal histidine, in the absence of an exogenous ligand [5].
• Nitric oxide binding properties of neuroglobin. A characterization by EPR and flash photolysis [11].
• Analogous studies for mutated neuroglobin (mutation of E7-His to Leu, Val, or Gln) reveal the predominant presence of the nitrosyl ferrous form [11].
• The heme environment of mouse neuroglobin: histidine imidazole plane orientations obtained from solution NMR and EPR spectroscopy as compared with X-ray crystallography [12].

Other interactions of Ngb

• In contrast, neuroglobin immunoreactivity was detected in specific brain regions with varying intensities and in the islet of Langerhans in the pancreas [13].

Analytical, diagnostic and therapeutic context of Ngb

• In situ hybridization localized neuroglobin mainly in brain and retina, while cytoglobin was expressed ubiquitously in all analyzed tissues [13].
• Based on the ligand-linked conformational changes discovered by crystallography, the pathways of the reactions with O2 and NO provide a framework that may account for the involvement of Ngb in controlling the activation of a protective signaling mechanism [4].
• To characterize the structure/function relationships of this new heme protein, we have used resonance Raman spectroscopy to determine the structure of the heme environment in Ngb from mice [14].
• The RT-PCR data supported the lack of differences in brain Ngb levels between normal and oxygen-deprived animals [7].
• In the retina, Ngb localization by immunohistochemistry was confined to the inner segments of the photoreceptors, the plexiform layers and the ganglion cells [7].

References