LRP2 is a potential molecular target for nonsyndromic pathological myopia
Kimberley Delaunay, Emilie Picard, Patricia Lassiaz, Laurent Jonet, Vidjea Cannaya, José Maria Ruiz-Moreno, Kentaro Kojima, Henrik Vorum, Bent Honoré, Jorge Ruiz-Medrano, Lasse Jørgensen Cehofski, Eric Pussard, Renata Kozyraki, Alicia Torriglia, Olivier Cases, Francine Behar-Cohen
Kimberley Delaunay, Emilie Picard, Patricia Lassiaz, Laurent Jonet, Vidjea Cannaya, José Maria Ruiz-Moreno, Kentaro Kojima, Henrik Vorum, Bent Honoré, Jorge Ruiz-Medrano, Lasse Jørgensen Cehofski, Eric Pussard, Renata Kozyraki, Alicia Torriglia, Olivier Cases, Francine Behar-Cohen
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Research Article Neuroscience Ophthalmology

LRP2 is a potential molecular target for nonsyndromic pathological myopia

Abstract

High myopia (HM) and posterior staphyloma (PS) are major causes of vision loss worldwide. Genetic and environmental factors, especially light exposure, influence myopia. This study shows that low-density lipoprotein–related receptor type 2 (LRP2) levels are decreased in the vitreous of patients with HM and PS, and that in human donor eyes affected by PS, LRP2 expression was reduced in the neural retina and retinal pigment epithelium (RPE), with morphologic changes similar to those observed in the Foxg1-Cre-Lrp2fl/fl mouse that also develops PS. In human induced pluripotent stem cell–derived RPE cells, LRP2 silencing regulated genes involved in eye and neuronal development, visual perception, tissue remodeling, hormone metabolism, and RPE structure. Its expression increased under light exposure, particularly red light, but was downregulated by cortisol. These findings establish a link between LRP2, myopization, and environmental factors, highlighting its crucial role in nonsyndromic HM and PS. LRP2 appears to be a promising therapeutic target for HM treatment.

Authors

Kimberley Delaunay, Emilie Picard, Patricia Lassiaz, Laurent Jonet, Vidjea Cannaya, José Maria Ruiz-Moreno, Kentaro Kojima, Henrik Vorum, Bent Honoré, Jorge Ruiz-Medrano, Lasse Jørgensen Cehofski, Eric Pussard, Renata Kozyraki, Alicia Torriglia, Olivier Cases, Francine Behar-Cohen

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Figure 3

Immunolabeling of retinal cells in the emmetropic and HM retina.

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Immunolabeling of retinal cells in the emmetropic and HM retina. (A and ...
(A and B) Glutamine synthetase (GS) labels Müller glial cells in the emmetropic retina, extending radially from the nerve fiber layer (nfl) to the outer nuclear layer (onl). (C and D) In HM retina, GS-positive cells extend in all directions and thicken at the retinal surface. At higher magnification, GS-positive cells surround a cyst in the ganglion cell layer (gcl) (C) and fill the bottom of the staphyloma where almost no retina remains (E). (F and G) Tubulin β3 (Tubb3) is a neuronal marker of retinal ganglion (RGC) and amacrine cells in the emmetropic retina. (H) In HM retina, the number of Tubb3-positive cells and RGCs is reduced. Higher magnification shows Tubb3-positive axons browsing at the surface of the staphyloma. (J and K) Blue (red staining) and green (green staining) opsin markers reveal the distribution of blue and green cones in the emmetropic retina. (L and M) In HM retina, the number of blue cones is reduced (L) and high magnification shows the accumulation of green opsin in abnormally shaped outer segments. (N and O) Glial fibrillary acidic protein (GFAP) labels astrocytes and glial Müller cell endfeet in the emmetropic retina. (P and Q) In the HM retina, the GFAP-positive endfeet are reduced. (Q) At higher magnification, a GFAP-positive membrane lays on the retinal surface but no positive cells are observed in the retina. Scale bars: 200 μm (A, F, J, and N), 80 μm (B, G, and O), 20 μm (K), 250 μm (C, H, L, and P), and 60 μm (D, E, I, M, and Q).