Neuroglobin Is an Endogenous Neuroprotectant for Retinal Ganglion Cells against Glaucomatous Damage

Abstract

Neuroglobin (NGB), a newly discovered member of the globin superfamily, may regulate neuronal survival under hypoxia or oxidative stress. Although NGB is greatly expressed in retinal neurons, the biological functions of NGB in retinal diseases remain largely unknown. We investigated the role of NGB in an experimental model of glaucoma, a neurodegenerative disorder that usually involves elevation of intraocular pressure (IOP). Elevated IOP is thought to induce oxidative stress in retinal ganglion cells (RGCs), thereby causing RGC death and, eventually, blindness. We found that NGB plays a critical role in increasing RGC resistance to ocular hypertension and glaucomatous damage. Neuroglobin (NGB) is a novel member of the globin superfamily that is distantly related to hemoglobin and myoglobin. 1 A highly conserved protein in evolution, human and mouse Ngb, both comprised of 151 amino acids, are 94% identical. 2,3 In mammals, expression of NGB is found in the brain, retina, and other nerve tissues, predominantly in neurons but absent from glial cells. 4 -7 Distribution of NGB protein in the normal human retina is very similar to what has been described in mice: NGB is detected primarily in the plexiform layers and photoreceptor inner segments, which are rich in mitochondria and synapses and consume high amounts of oxygen. 8,9 NGB has been shown to act as an endogenous neuroprotective molecule that enhances neuronal survival under hypoxic-ischemic insults in the brain 10 -12 ; however, its physiological functions and molecular mode of actions are not fully understood. Of note, NGB is present at a 100-fold greater concentration in the retina than in the brain, 8,[13][14][15] suggesting that the retina may be its most important site of function; however, among the many unknown roles of NGB, functional significance of NGB expression in the retina has been largely unexplored.

Effect of light on global gene expression in the neuroglobin-deficient mouse retina

“…A number of studies have reported high levels of Ngb in the retina and adverse effects of Ngb knockdown on neuronal survival, leading the hypothesis that Ngb is important for retinal oxygen homeostasis and neuronal survival (7)(8)(9)(10)(11)(12)(13)(14)(30)(31)(32). Recently, Chan et al (13) found that transgenic overexpression of Ngb conferred protection against retinal ischemia via a decrease in oxidative stress levels.…”

“…Another study showed an overlap between Ngb expression and areas with the highest number of mitochondria supporting a respiratory function of Ngb (8). Previously, several studies have implicated a neuroprotective function of Ngb in retinal diseases (9)(10)(11)(12). Furthermore, transgenic mice overexpressing Ngb were found to be resistant to retinal ischemia (13) and in vivo knockdown of Ngb using small interfering RNA (siRNA) induced the degradation of retina ganglion cells and behavioral effects associated with compromised visual performance (14).…”

Neuroglobin, a Factor Playing for Nerve Cell Survival

“…NGB overexpression resulted also protective against traumatic brain injury [45,46] and β-amyloid-induced neurotoxicity and Alzheimer phenotype in NGB and APP (amyloid precursor protein) double-transgenic mice [47]. Furthermore, in vivo studies on retinal damage [48,49] and ischemia [50] demonstrated that NGB overexpression protected retinal ganglion cells. Whereas the majority of the studies indicated a protective effect of NGB, data raising some question on the capacity of NGB to provide general protection to neurons in vivo were also reported.…”

“…They include ATP production [45] and reactive oxygen species (ROS) generation [34,39,48]. NGB treatment was able to stabilize mitochondrial membrane potential [34] and NGB overexpression was associated with reduced mitochondrial DNA damage [50].…”

The Anti-Apoptotic Role of Neuroglobin

“…The neuroglobin protein has been shown to be protective in retinal ischemia and also in the case of glaucoma [90,91,92]. …”