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 2

Ophthalmologic imaging and histological analysis of the right eye of an HM donor.

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Ophthalmologic imaging and histological analysis of the right eye of an ...
(A and B) Premortem SD-OCT scans of the right eye with inferior cross section (A) and macular cross section (B), showing the posterior staphyloma (PS) (white arrows) and tractional maculopathy (yellow stars). The myopic eye displayed an atrophy of the macula delineated by small arrows and the posterior incurvation indicated the uncomplicated PS. (C) Gross morphology of the HM right enucleated postmortem eye with PS. (D) Macroscopic image of the posterior chamber after dissection showing the PS. (E) Insert box of D focusing on fovea and PS (black arrow). (F) DAPI-stained section of a normal human retina near the macula. (G) DAPI-stained section of the HM retina with a PS (double headed arrow) shows a severe reduction in thickness of all retinal layers, adjacent to the PS. Schisis (white arrow) is observed between the inner nuclear layer (inl) and the outer nuclear layer (onl). A cyst is observed between the RPE and the outer segments layer (asterisk). bv, blood vessel. (H) RPE cells in human retina form a single layer of pigmented cells as observed on light transmission microscopy. Melanosomes (m) have an elongated shape and nuclei (n) are spaced at regular intervals. (I and J) In the HM donor eye, RPE cells are still forming a single layer. RPE cells are abnormally large, their apical domain is reduced, and melanosomes aggregate in macromelanosomes (mm) or macrostructures (ag). Scale bars: 75 μm (F), 120 μm (G), and 5 μm (H–J).