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Christophe Lechauve, Aicha Bouaita, Sebastien Augustin, Helene Cwerman-Thibault, Jose A. Sahel, Jr., Marisol Corral-Debrinski; The involvement of neuroglobin in mitochondrial integrity: the case of the Harlequin Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5395.
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Harlequin (Hq) mouse exhibits a 80% decrease of AIF (Apoptosis Inducing Factor) which is essential for respiratory chain complex I activity. Thus, the mitochondrial impairment induced leads to progressive retinal neuron loss and ultimately blindness. Neuroglobin (Ngb) is a monomeric hemoprotein of the globin family that is mainly expressed in neurons of the central and peripheral nervous systems. We demonstrated that Ngb function is a reliable marker of mitochondrial activity, since its downregulation in retinal ganglion cells (RGC) is correlated to complex I and III defects and cell loss. Moreover, in rat retinas a significant amount of the protein localizes to mitochondria. Our main objectives were to extensively define gene expression changes in Hq mice and to determine whether Neuroglobin overexpression could protect RGC integrity in these mice. For the latter we used an optimized AAV2 vector containing the Ngb ORF with its entire 5’ and 3’ UTRs.
Morphological and functional examinations of retinal damage were performed in Hq mice over time. Mitochondria and oxidative stress PCR Array profiles were performed to study the expression of genes involved in mitochondrial biogenesis and function (electron transport chain, oxidative phosphorylation complexes) and retinal oxidative stress. Protein expression, microglial activation, and reactive gliosis were evaluated by immunohistochemistry on retinal cross-sections.
First signs of RGC and nerve fiber decrease were evidenced in mice aged of 4 months leading to visual performance decline at 6-8 months. We show differences of gene expression between Hq and control mice correlate to retinal degeneration. For instance, Ngb expression decrease of 50% in Hq compare to control and is associated with a decrease in the Ngb intensity of labeling. These changes permit us to consider an AAV therapeutic gene therapy to prevent RGC loss.
We demonstrate major change of gene expression reliable with mitochondrial activity and intimately associated with RGC survival in Hq mice. Thus these mice represent a faithful genetic model which mimics human retinal degeneration due to mitochondrial impairment.
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